Saffron

Saffron (Crocus sativus L.)

1. Identity

Botanical and Chemical Names

Crocus sativus L. (common name: Saffron; family: Iridaceae) is an important flowering plant used extensively as a spice, food coloring agent, and flavoring agent. Among 85 species reported under the genus Crocus, C. sativus is the most commercially important species. It is a triploid (3n) and sterile herb propagated naturally by corms, originating from mother corms. The plant blooms in the autumn and does not grow in the wild.

Source and Harvested Part

Cultivated primarily in regions like Iran, Greece, and India, saffron is derived from the red stigmas of the Crocus flower. The pistils of the saffron flowers possess three reddish-orange stigmas with a pleasant aromatic smell. After picking the flowers by hand, the stigmas are separated, dried, and employed as saffron. The most commonly used plant part of C. sativus is the stigma, known as saffron.

Common Forms and Preparations

Saffron is commercially available in several forms:

• Dried threads (stigmas): the traditional whole form, used in cooking and infused in warm water or milk.
• Powdered saffron: ground dried stigmas.
• Standardized extracts: used in most clinical research, standardized to specific levels of crocin or safranal (e.g., the proprietary extract "Affron®"). Clinical trials have used supplementation with saffron extract (such as Affron®) at doses such as 28 mg saffron daily in 12-week, parallel-group, randomized, double-blind, placebo-controlled designs.
• Capsule or tablet preparations: standardized dried stigma capsules, typically 15 mg or 30 mg per unit, used in most human trials.

In the European E number categorization for food elements and additives, saffron is coded as E164.

2. Traditional and Historical Use

Ancient and Prehistoric Use

Saffron-based pigments have been found in the prehistoric paints used to illustrate beasts in 50,000-year-old cave art found in modern-day Iraq. The Sumerians used saffron as an ingredient in their remedies and magical potions. They gathered their stores from wild flowers, believing that divine intervention alone enabled saffron's medicinal properties. Saffron was also known in ancient Egypt, as indicated by a 2000 BC papyrus.

The dried stigma of Crocus sativus L. flowers has been used for 4,000–5,000 years as a dye, seasoning, perfume, and medicinal plant. In ancient cultures (Akkadian, Mesopotamian, Greek, Roman) it was equally a symbol of wealth. Saffron was the dye of some old wall paintings and royal garments.

Persian and Middle Eastern Traditions

Saffron, the dried, dark red stigmas of Crocus sativus L. from the Iridaceae family, is a well-known traditional herb that was mentioned in Iranian medical books. Saffron was highly regarded in ancient Persia for its medicinal properties and was extensively used in traditional medicine. Historical records describe saffron serving as a preventative cure during severe plague epidemics, with people believing it could protect against contagion, and its high value led to rigorous trade regulations. In the late Middle Ages, it was believed that saffron was one of the most effective phytotherapeutic agents against some serious infectious diseases such as plague or cholera.

Indian Traditions (Ayurveda and Unani Medicine)

When Persian traders introduced saffron to the Indian subcontinent, the Kashmir region soon became known for producing high-quality saffron, prized for its deep color and potent aroma. Throughout Asia, saffron was widely employed in Ayurvedic medicine to address various health issues, including digestive disorders, inflammation, and mood disturbances. In Ayurvedic (Indian) and Unani (Greek) medicine, saffron was historically prescribed for respiratory, cardiovascular, and gynecological disorders, as well as enhancing memory and libido.

Traditional Chinese Medicine

Saffron has a long history of applications in traditional Chinese medicine, following its introduction to China. According to the theory of traditional Chinese medicine, saffron is sweet and slightly cold in nature, and enters the heart and liver meridians. It can invigorate blood circulation, eliminate blood stasis, and cool blood, eliminating heat toxins. Saffron has been used in these traditions to treat asthma, phlegm, insomnia, Alzheimer's disease, depression, fright, shock, hemoptysis, heartburn, and pain.

Religious and Cultural Uses

Buddhist religious traditions consider saffron robes a sign of renunciation, while Kashmiri cuisine often incorporates saffron into foods to represent hospitality and celebration. Despite its high cost, saffron has been used as a fabric dye, particularly in China and India.

3. Key Constituents and Active Compounds

General Phytochemical Profile

The chemical components of saffron are sugars (63%), protein (12%), moisture (10%), fat (5%), minerals (5%), and 5% crude fiber (% w/w). A variety of biologically active volatile and non-volatile compounds have been extracted from saffron flowers, primarily from the stigma. These compounds include apocarotenoids, flavonoids, terpene alcohols, and their esters.

Principal Bioactive Compounds

More than 150 volatile compounds are present in saffron stigmas; the major bioactive compounds in this traditional herb are crocin (C₄₄H₆₄O₂₄), picrocrocin (C₁₆H₂₆O₇), and safranal (C₁₀H₁₄O), which are responsible for the color, taste, and odor of saffron, respectively.

• Crocins: Crocin and crocetin are carotenoid compounds that cause the yellow-orange color of saffron. Crocins, derived from crocetin glycosides, have demonstrated antioxidant, neuroprotective, anticancer, antidepressant, hepatoprotective, cardioprotective, and antihyperlipidemic properties.
• Crocetin: Several important properties of saffron have been correlated to crocetin; its mechanisms of action include elevation of the rate of oxygen transport, induction of apoptosis in cancer cells, and cell protection from reactive oxygen species (ROS). Crocetin may be effective in hemorrhages, tumors, and atherosclerosis.
• Safranal: Safranal, the main component of C. sativus essential oil, is responsible for the unique odor of saffron. It has been investigated for effectiveness against depression, anxiety, convulsion, and nociception and inflammation.
• Picrocrocin: The flavor of saffron is due to picrocrocin.
• Flavonoids: Carotenoids (crocins, crocetin, picrocrocin, and safranal) and glycosides (quercetin and kaempferol) are the main bioactive constituents, which possess antioxidant, anti-inflammatory, and neuroprotective properties.

Mechanisms of Action

Evidence from in vitro and in vivo models, as well as clinical studies, suggests that saffron primarily exerts its beneficial effects through the modulation of oxidative stress, apoptosis, autophagy, lipid metabolism, and the regulation of key molecular pathways, including the NF-κB, PI3K/Akt/mTOR, and Nrf2/HO-1 pathways.

It has been suggested that saffron and crocin extracted from it also up-regulate the expression of sirtuin 1 (SIRT1) and nuclear factor erythroid 2-related factor 2 (Nrf2), down-regulate the nuclear factor kappa B (NF-κB) signaling pathway, and ultimately improve body organ dysfunction. Inhibition of inducible nitric oxide synthase and cyclooxygenase-2 (COX2) is also attributed to crocin.

Recent studies have shown that the effects of crocin, crocetin, and safranal against oxidative stress include the reduction in lipid peroxidation (malondialdehyde [MDA] levels) and nitric oxide (NO) levels.

The beneficial effects of saffron on inhibition of serum levels of nuclear transcription factor κB (NF-κB) p65 unit, tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), and some interleukins (IL) such as IL-1β, IL-6, IL-12, and IL-17A have been reported.

4. Scientific Evidence by Area of Use

4.1 Depression and Mood Disorders

The evidence base for saffron in depression is the most developed of all its clinical applications. Thirteen systematic reviews have investigated the effects of saffron on depression.

Multiple systematic reviews and meta-analyses of randomized controlled trials indicate that saffron produces a large positive effect compared to placebo for both depressive and anxiety symptoms, and can also enhance the effects of standard antidepressants when used as adjunct therapy. Clinical trials suggest that saffron's efficacy in reducing depressive and anxiety symptoms is comparable to that of selective serotonin reuptake inhibitors (SSRIs), but with fewer reported adverse effects.

A key meta-analysis directly comparing saffron with SSRIs drew on multiple RCTs: Meta-analysis of 8 studies assessing depression outcomes revealed a nonsignificant difference between saffron and SSRIs in reducing depressive symptoms (SMD = 0.10; 95% CI: −0.09 to 0.29). Four studies reporting anxiety outcomes showed a nonsignificant difference between saffron and SSRIs in reducing anxiety symptoms (SMD = 0.04; 95% CI: −0.22 to 0.29). With regard to safety, participants receiving saffron had fewer adverse events than the SSRI group (risk difference: −0.06; 95% CI: −0.09, −0.04; I²: 0%).

An adjunctive study using crocin (an active ingredient of saffron; 15 mg twice daily) demonstrated additive effects alongside selective serotonin reuptake inhibitors (SSRIs).

Evidence quality: Saffron has been shown in previous trials to have antidepressant effects in clinically diagnosed adults. However, the recruitment of small sample sizes, short treatment periods, and variability in the quality of studies have negatively impacted the strength of conclusions. Publication bias has also been noted as a concern.

4.2 Anxiety

Systematic reviews have assessed the overall effects of saffron on cognition, depression, anxiety, sleep disorders, attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD). Evidence for anxiety is promising but is frequently derived from the same trials addressing depression, and dedicated anxiety-only RCTs are limited. The comparison with SSRIs showed non-inferiority for anxiety outcomes, though study sample sizes remain small.

4.3 Cognitive Function and Neurodegenerative Disorders

Saffron has demonstrated promising efficacy in the treatment of Alzheimer's disease (AD) and mild cognitive impairment (MCI), with multiple RCTs and meta-analyses suggesting comparable cognitive outcomes to standard pharmacologic therapies such as donepezil and memantine.

A landmark 16-week RCT administered: Patients were randomly assigned to receive capsule saffron 30 mg/day (15 mg twice per day) or capsule placebo (two capsules per day) for a 16-week study. A subsequent 22-week multicenter RCT compared saffron to donepezil directly: Fifty-four Persian-speaking adults 55 years of age or older with AD participated in a 22-week, double-blind study. The main efficacy measures were the change in the Alzheimer's Disease Assessment Scale-cognitive subscale and Clinical Dementia Rating Scale-Sums of Boxes scores compared with baseline. Adverse events were systematically recorded. Participants were randomly assigned to receive capsule saffron 30 mg/day (15 mg twice per day) or donepezil 10 mg/day (5 mg twice per day). This phase II study provides preliminary evidence of a possible therapeutic effect of saffron extract in the treatment of patients with mild-to-moderate Alzheimer's disease.

In cognitive disorders, saffron (30 mg/day) showed non-inferiority to donepezil (10 mg/day) and memantine (20 mg/day) in patients with mild-to-moderate and moderate-to-severe AD. Trials lasting 16 to 52 weeks demonstrated significant improvements on validated cognitive scales such as the Alzheimer's Disease Assessment Scale – Cognitive Subscale (ADAS-Cog) and Clinical Dementia Rating – Sum of Boxes (CDR-SB), with fewer gastrointestinal side effects compared to standard treatments.

A systematic review and meta-analysis concluded that saffron may have the potential to improve cognitive function and activities of daily living in patients with Alzheimer's disease and MCI. However, due to limited high-quality studies there is insufficient evidence to make any recommendations for clinical use, and further clinical trials on larger sample sizes are warranted.

Saffron and its compounds can play an important role in inhibiting neuroinflammation and excitotoxic pathways, modulating autophagy and apoptosis, attenuating oxidative damage, and activating defensive antioxidant enzymes, resulting in neuroprotection against neurodegenerative diseases. However, the majority of neuroprotection data remains preclinical.

4.4 Eye Health — Age-Related Macular Degeneration (AMD) and Glaucoma

Saffron has attracted attention for its potential role in protecting vision, particularly in age-related eye conditions such as macular degeneration, glaucoma, and diabetic maculopathy. The retina is particularly vulnerable to oxidative stress, and saffron's carotenoids and antioxidants may help protect retinal cells, improve blood flow to the eyes, and reduce inflammation.

Limited clinical studies have evaluated the effect of oral saffron supplementation (30 mg and 20 mg daily for 1 and 3 months, respectively) on age-related macular degeneration. Retinal flicker sensitivity was improved in these studies, suggesting a neuroprotective effect.

An open-label extension trial of 93 adults (>50 years) with mild/moderate AMD and vision >20/70 Snellen equivalent in at least one eye evaluated participants given oral saffron supplementation (20 mg/day) for 12 months.

A decrease in intraocular pressure was demonstrated at 3 weeks in a clinical study (N=17) evaluating the effect of oral saffron (30 mg/day for 1 month) in patients with primary open-angle glaucoma.

Evidence quality: Studies in this area are preliminary and characterized by small sample sizes. Results are promising but far from definitive.

4.5 Cardiovascular Risk Factors and Metabolic Syndrome

A systematic review and dose-response meta-analysis found that consumption of saffron significantly decreased triglycerides (WMD = −8.81 mg/dl, 95% CI: −14.33, −3.28; P = 0.002), total cholesterol (WMD = −6.87 mg/dl, 95% CI: −11.19, −2.56; P = 0.002), LDL cholesterol (WMD = −6.71 mg/dl, 95% CI: −10.51, −2.91; P = 0.001), fasting blood glucose (WMD = −7.59 mg/dl, 95% CI: −11.88, −3.30; P = 0.001), HbA1c (WMD = −0.18%, 95% CI: −0.21, −0.07; P < 0.001), HOMA-IR (WMD = −0.49, 95% CI: −0.89, −0.09; P = 0.016), and systolic blood pressure (WMD = −3.42 mmHg, 95% CI: −5.80, −1.04; P = 0.005).

A separate meta-analysis found a significant reduction in serum concentrations of total cholesterol (TC) and triglycerides (TG) and a significant increase in HDL following supplementation with saffron. Saffron supplementation had no significant influence on serum fasting plasma glucose and LDL concentrations in that analysis.

Individual RCT findings are mixed: The improvement effect of saffron on the components of metabolic syndrome and related diseases has been explored through various clinical trials, yielding inconsistent findings. For example, a randomized controlled trial in 80 type 2 diabetes patients with a mean age of 54.1 years, where participants were randomized to take either saffron tablets (100 mg/day) or placebo for 12 weeks, demonstrated that saffron (100 mg/day) intake for 12 weeks had beneficial effects on waist circumference and malondialdehyde levels; however, it did not influence glycemic, lipid, and inflammatory indices in comparison with the placebo group.

Evidence quality: Meta-analyses suggest some statistically significant benefit on lipid and glycemic markers, but individual trial results are inconsistent. Most studies are short-term (8–16 weeks) and involve modest sample sizes. The clinical significance of the magnitudes of effect has not been firmly established.

4.6 Premenstrual Syndrome (PMS)

Possible effects of saffron on premenstrual syndrome have been reported in systematic reviews. Saffron appears to improve symptoms of premenstrual syndrome, including mood, anxiety, irritability, depression, nervous tension, and mood swings. One RCT compared saffron (15 mg twice daily) against fluoxetine (20 mg twice daily) and placebo over two weeks in the luteal phase of the menstrual cycle. The results showed that saffron extracts were superior to the placebo in treating PMS symptoms. While fluoxetine also improved PMS symptoms, it also caused more side effects.

Evidence quality: Preliminary; trials are small and of short duration. Results warrant confirmation in larger, well-designed studies.

4.7 Sexual Dysfunction

Six systematic reviews have studied saffron's impact on sexual dysfunction. One of the traditional aphrodisiacs used in various cultures is Crocus sativus. Previous studies have pointed to the possible applicability of saffron for sexual dysfunction in both men and women. In a three-center RCT, married women between 18 and 55 years of age suffering from severe sexual dysfunction were randomized to receive either 15 mg Crocus sativus capsules twice daily or placebo. The treatment continued for 6 weeks, and patients were evaluated every 2 weeks. The primary outcome was the change in the female sexual function index score.

Evidence quality: Limited clinical studies suggest efficacy in sexual dysfunction. Data in men (including SSRI-induced sexual dysfunction) and women are promising but based on small trials. Further large-scale RCTs are needed.

4.8 Sleep Quality

Possible effects of saffron on sleep disorders have been reported in systematic reviews. Meta-analyses of RCTs examining saffron's effects on sleep quality have been published, though the evidence base is smaller than that for depression or cognition. Studies have typically used standardized extracts in adults with self-reported poor sleep, and short-term outcomes have generally been favorable. Evidence quality: Preliminary; studies are small and short-term.

4.9 Cancer (Preclinical Evidence)

Saffron has selective toxic and preventive effects on cancerous cells without adverse effects on normal cells and prevents tumor formation. Saffron appears to reduce the toxic effects of anticancer drugs. The effect of crocetin in cancer prevention has been elaborated against oxidative stress by reduction of malondialdehyde levels, improving the levels of glutathione and antioxidant enzymes, along with reducing lipid peroxidation. Moreover, carotenoids found highly in saffron can enhance cancer prevention mechanisms by acting as strong antioxidants. Chemoprevention activity of saffron and its pure components appears to occur through anti-proliferative, antioxidant, and anti-inflammatory effects.

Evidence quality: Saffron extract can be considered for treatment and prevention of cancer only after confirmation in human clinical trials. The vast majority of anticancer evidence at this time is in vitro or in animal models. There are no large-scale human RCTs establishing saffron's anticancer efficacy.

5. Body Systems and Health Areas

Based on the published clinical and preclinical literature, saffron has been investigated across the following body systems and health domains:

• Central Nervous System / Neuropsychiatric: Depression, anxiety, mild cognitive impairment, Alzheimer's disease, ADHD, OCD, sleep disorders.
• Cardiovascular / Metabolic: Lipid metabolism (cholesterol, triglycerides), blood glucose regulation, insulin resistance, blood pressure, metabolic syndrome, type 2 diabetes.
• Ophthalmological: Age-related macular degeneration, glaucoma, diabetic maculopathy.
• Reproductive / Gynecological: Premenstrual syndrome, sexual dysfunction (both male and female).
• Immunological / Inflammatory: Modulation of NF-κB, TNF-α, IFN-γ, and interleukin levels.
• Oncological (preclinical): Anti-proliferative and apoptotic effects in various cancer cell lines.
• Gastrointestinal: Historically used for digestive disorders; limited modern clinical evidence.

6. Dosage Forms and Dosages Reported in Studies

The following dosages have been reported in clinical studies. These represent what has been studied in research settings, not clinical recommendations.

• Depression / Anxiety: Most RCTs have used crocin 15 mg twice daily (30 mg/day total) as an adjunct to SSRIs, or standardized saffron extracts. One 12-week RCT supplemented 202 adults with 28 mg saffron daily.
• Alzheimer's Disease / Cognitive Decline: Participants were randomly assigned to receive capsule saffron 30 mg/day (15 mg twice per day) in a 22-week trial comparing saffron with donepezil 10 mg/day (5 mg twice per day).
• Age-Related Macular Degeneration: Participants were given oral saffron supplementation of 20 mg/day for 12 months in one open-label extension trial. Other early studies used 30 mg daily for 1 month.
• Metabolic Syndrome / Type 2 Diabetes: Participants were randomized to take either saffron tablets (100 mg/day) or placebo for 12 weeks in one RCT.
• Premenstrual Syndrome: 15 mg of saffron taken twice daily was compared against 20 mg of fluoxetine taken twice daily and placebo for 2 weeks during the luteal phase.
• Sexual Dysfunction (female): 15 mg Crocus sativus capsules twice daily for 6 weeks.

7. Safety Considerations and Interactions

General Safety Profile at Therapeutic Doses

Meta-analyses confirm that saffron at therapeutic doses is associated with no serious adverse events. Saffron represents a safe, well-tolerated intervention with growing evidence for use in psychiatric and neurologic disorders. Daily consumption of saffron up to 1.5 g/day has not been found to be associated with any adverse effect.

Adverse Effects at Therapeutic Doses

Clinical data reported no significant adverse effects in the saffron group compared with placebo groups in studies of postpartum depression. The reported side effects were bleeding gums (one participant), gastrointestinal disorder (two), hypersomnia (one), insomnia (one), and breast milk reduction (two). Comparison between side effects of saffron extract and citalopram showed that some adverse effects were less frequent in the saffron group, including vertigo, drowsiness, gastritis, anger/rage, and palpitation.

The most frequent adverse effects mentioned in studied books were headache, nausea, head fullness, dizziness, hypomania, and appetite suppression. Yellowing is another side effect reported for saffron; colored constituents of saffron may accumulate in the sclera, skin, or mucosa, mimicking icteric complaints.

Toxicity at High Doses

In pharmacopoeias and herbal monographs (including that of the German Commission E), toxic effects are reported with 5 g and above, and the lethal dose is said to be approximately 20 g; adverse effects include vomiting, uterine bleeding, bloody diarrhea, hematuria, and bleeding from the nose, lips, and eyelids. According to a study by Schmidt et al. (2007), consuming more than 10 grams of saffron may stimulate absorption and adverse effects including decreased appetite, insomnia, nausea, vomiting, dizziness, and miscarriage.

Saffron doses over 10 g have been used for abortion with high risk of maternal death. At this latter dose, saffron can induce vomiting, uterine bleeding, hematuria, gastrointestinal bleeding, and vertigo.

Pregnancy

A great concern has been the effect of saffron administration to pregnant women and their neonates. High doses of saffron have historically been used as an abortifacient and are associated with uterine stimulation. Evidence on safety at culinary doses in pregnancy is limited. Some studies reported no toxicity for the consumption of up to 4 g/day over several days, even in pregnant women, though this should be interpreted with caution given the limited data.

Interactions

Saffron supplements may interact with blood pressure medication and are contraindicated in high doses for pregnant women due to uterine stimulation. Given saffron's established modulation of serotonergic and dopaminergic pathways, theoretical interactions with psychiatric medications, particularly SSRIs and MAOIs, are biologically plausible, though formal pharmacokinetic drug interaction studies in humans remain limited.

Adulteration and Quality Concerns

While saffron is generally regarded as safe, challenges remain concerning its high cost, limited availability, and variability in quality due to geographic and environmental factors. Adulteration of commercial saffron is a well-documented problem in the industry, which has direct implications for the interpretation of study results and clinical use of non-standardized preparations.

References

• Immunoregulatory and anti-inflammatory properties of Crocus sativus (Saffron) and its main active constituents: A review — PMC
• A review of therapeutic impacts of saffron (Crocus sativus L.) and its constituents — PMC
• Functional, Nutraceutical and Health Endorsing Perspectives of Saffron — PMC
• Crocus sativus L. Extract and Its Constituents: Chemistry, Pharmacology and Therapeutic Potential — PMC
• Phytochemistry, Biological Activities, Molecular Mechanisms, and Toxicity of Saffron (Crocus sativus L.): A Comprehensive Overview — MDPI/PMC
• Current Knowledge of the Antidepressant Activity of Chemical Compounds from Crocus sativus L. — PMC
• Interaction of saffron and its constituents with Nrf2 signaling pathway: A review — PMC
• Effect of Saffron Versus Selective Serotonin Reuptake Inhibitors (SSRIs) in Treatment of Depression and Anxiety: A Meta-analysis of Randomized Controlled Trials — PubMed
• The neuropsychotropic effects of Crocus sativus L. (saffron): an overview of systematic reviews and meta-analyses — PMC
• From Mood to Memory: Unlocking Saffron's Potential in Brain Health — PMC
• Saffron for mild cognitive impairment and dementia: a systematic review and meta-analysis of randomised clinical trials — PMC
• A 22-week, multicenter, randomized, double-blind controlled trial of Crocus sativus in the treatment of mild-to-moderate Alzheimer's disease — PubMed
• Saffron in the treatment of patients with mild to moderate Alzheimer's disease: a 16-week, randomized and placebo-controlled trial — PubMed
• Therapeutic effects of saffron and its components on neurodegenerative diseases — PMC
• The effects of saffron supplementation on cardiovascular risk factors in adults: A systematic review and dose-response meta-analysis — PMC
• The effect of saffron supplementation on blood glucose and lipid profile: A systematic review and meta-analysis of randomized controlled trials — PubMed
• Effects of Saffron Supplementation on Glycolipid Metabolism and Blood Pressure in Patients With Metabolic Syndrome: A Systematic Review and Meta-Analysis — PMC
• Effects of Saffron Supplementation on Inflammation and Metabolic Responses in Type 2 Diabetic Patients: A Randomized, Double-Blind, Placebo-Controlled Trial — PMC
• Saffron therapy for the ongoing treatment of age-related macular degeneration — PubMed
• Crocus sativus (saffron) in the treatment of female sexual dysfunction: a three-center, double-blind, randomized, and placebo-controlled clinical trial — PMC
• Saffron and its active ingredients against human disorders: A literature review on existing clinical evidence — PMC
• Toxicity of Saffron Extracts on Cancer and Normal Cells: A Review Article — PMC
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• Saffron Reduced Toxic Effects of its Constituent, Safranal, in Acute and Subacute Toxicities in Rats — PMC
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• Comparative anticancer activity analysis of saffron extracts and crocetin — PMC
• History of saffron — Wikipedia