Saffron

Scientific Name(s): Crocus sativus L.

Common Name(s): Saffron, Stigma Croci, Za'faran

Medically reviewed by Drugs.com. Last updated on Jan 20, 2020.

Clinical Overview

Use

Saffron has widespread traditional uses. It has demonstrated efficacy as an alternative treatment for mild to moderate depression. Antinociceptive and anti-inflammatory activity has been suggested. Saffron may also have a potential role in the treatment of cancer, in the reduction of cardiovascular risk factors, and in age-related macular degeneration.

Dosing

Clinical studies have evaluated doses ranging from 20 to 400 mg/day of pure saffron. Dosages of up to 1.5 g/day of saffron are thought to be safe; toxic effects have been reported for 5 g doses. Depression: 20 to 30 mg/day of saffron extract (stigma or petal) for mild to moderate depression. Hypertension: 400 mg/day of saffron tablets for 7 days.

Contraindications

Contraindicated in bleeding disorders.

Pregnancy/Lactation

Avoid use. Amounts higher than those used in food (eg, 5 g or more) have uterine stimulant and abortifacient effects. Information regarding safety and efficacy in lactation is lacking.

Interactions

None well documented.

Adverse Reactions

Reported adverse effects include nausea, vomiting, and headache. Allergic reactions are uncommon; however, occupational allergies, including rhinoconjunctivitis, bronchial asthma, and cutaneous pruritus, have been reported. Case reports of anaphylaxis also exist.

Toxicology

Information is limited. Doses of 5 g are associated with toxic effects; doses of 10 to 20 g may be fatal.

Scientific Family

Iridaceae

Botany

True saffron is native to Asia Minor (Anatolia) and southern Europe, with the majority of the world's saffron production based in Iran. Its blue-violet, lily-shaped flowers contain the orange stigmas (part of the pistil) and red style branches used to produce saffron spice. The plant is a bulbous perennial that grows 15 to 20 cm in height. Mature stigmas are collected by hand during a short autumn blooming season.1, 2

True saffron should not be confused with Carthamus tinctorius L. (family Asteraceae), also called American saffron (safflower, Indian safflower); the spice of American saffron is produced from its tubular florets and is characterized by a lighter red than true saffron. The two are often used for the same purposes, and the less expensive American saffron is sometimes used as a substitute for or to adulterate true saffron.

History

Saffron use has been traced to ancient Egyptian and Roman times, when it was used medicinally, only later becoming valued as a spice and dye. The word "saffron" is thought to originate from the Arabic "za'faran," meaning yellow. Other sources suggest the name "Crocus" has origins in Greek mythology, according to which drops of blood from "Krokos," friend of Hermes, fall on the flower of a plant and create the characteristic stigmata of saffron flowers.2, 3, 4, 5

Saffron has traditionally been used for its sedative, emmenagogue, stimulant (appetite), aphrodisiac, diaphoretic, and antidepressant properties, and for a wide variety of conditions, including cramps, asthma, menstrual disorders, liver disease, and pain.1, 3, 6 From the 17th to 19th centuries, saffron was included in various opioid preparations, including laudanum and "black-drop," for pain relief.6 In the Indian Ayurvedic health system, saffron is considered an adaptogen.3 However, The Complete German Commission E Monographs negatively evaluated saffron for use in cramps and asthma.4 Various patents exist for saffron in combination with other agents.

Chemistry

The stigmas of C. sativus contain the primary pigment crocin, as well as anthocyanin, alpha- and beta-carotene, and zeaxanthin pigments, and the vitamins riboflavin and thiamine. The major carotenoid derivatives found in saffron are crocetin, picrocrocin, and safranal.2, 5, 7 The characteristic taste of the spice is attributed to the glycoside picrocrocin, while safranal is considered the main odiferous constituent, achieved through hydrolysis of picrocrocin.8

Crocin is a mixture of glycosides: crocetin, a dicarboxylic terpene lipid, and alpha-crocin, a digentiobiose ester of crocetin. Cis- and trans-crocetin dimethyl esters have also been identified.7 Similar compounds have been isolated from other members of the Iridaceae family. Gardenidin, a compound obtained from gardenias, is identical to crocetin.

The essential oil derived from saffron is a complex mixture of more than 30 components, mainly terpenes and their derivatives. A review of the volatile compounds of saffron has been published.8

Uses and Pharmacology

Cancer

Animal and in vitro data

By mechanisms not fully understood, saffron appears to be selectively cytotoxic, inhibiting proliferation and disease progression while healthy cells remain viable. Antioxidant effects have been demonstrated.2, 5, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 The toxicity of cytostatic drugs, such as cisplatin, has been reduced with coadministration of saffron extracts, without affecting the antitumor activity of the cytostatic drugs.6, 9, 19 In one study, lifespan in rats with induced carcinomas was increased with the administration of saffron extracts5; in other studies of animal models and with cultured human malignant cell lines, saffron demonstrated antitumor and cancer preventive activities.10, 11

Clinical data

Research reveals no clinical data regarding the use of saffron in cancer.

Cardiovascular effects

Animal data

Reviews of studies investigating the cardiovascular effects of saffron in animals have been published. Reductions in blood pressure, decreased cholesterol and triglyceride levels, inhibition of platelet aggregation and improved overall hemodynamic status, and reduced infarct size have been reported. Stimulatory effects on beta-2 adrenoceptors, antimuscarinic and anticholinergic effects, calcium channel antagonism, modulation of nitric oxide, and increases in cyclic adenosine monophosphate have been observed in rodents or tissue preparations.2, 5, 20, 21 In a study comparing saffron with amiodarone in rats, saffron doses up to 200 mg/kg demonstrated a beneficial antiarrhythmic effect, but were not as effective as amiodarone.22 Beneficial effects of saffron extracts on insulin resistance and lipid levels seem to be associated with increased adiponectin.23, 24

Clinical data

Saffron has demonstrated an antioxidant effect in human platelets via inhibition of lipid peroxidation.25, 26, 27 Improved antioxidant status was demonstrated in an older study of patients with coronary artery disease administered saffron extract 50 mg twice daily.4, 9 In patients with metabolic syndrome, supplemental saffron 100 mg daily for 12 weeks produced improvement in some indices related to risk factors for cardiovascular disease (ie, heat shock proteins).28

In a study among healthy volunteers, saffron 400 mg daily for 7 days resulted in decreases in standing systolic, but not diastolic, blood pressure and in mean arterial pressure.29 In a double-blind, placebo-controlled study (N=60), administration of saffron 200 mg or 400 mg daily for 1 week did not affect any of the measured coagulation parameters.30

Depression

Animal data

In reviews of studies conducted in animal models of various CNS diseases, use of saffron extracts resulted in modulation of altered central excitatory and inhibitory processes, thus ameliorating CNS conditions such as depression.31 Aqueous and ethanolic saffron extracts reduced immobility time and increased swimming time in mouse models.32

Clinical data

A number of clinical trials have evaluated the efficacy of saffron 30 mg daily over 6 to 8 weeks in treating mild to moderate depression.5, 33, 34, 35, 36, 37, 38, 39, 40, 41 In several trials, saffron was more effective than placebo and at least equivalent to therapeutic doses of imipramine and fluoxetine according to Hamilton Depression Rating Scale (HAM-D) scores. There were no differences in adverse events between saffron and placebo groups in any of the studies; however, several involved small sample sizes (40 patients) and were conducted by the same group of researchers within a non-Western population.5, 40, 41 According to a meta-analysis of 5 published clinical trials examining the effects of saffron supplementation on symptoms of depression in patients with major depressive disorder, mean effect size was 1.62 for saffron over placebo (P<0.001).42 A more recent study of 60 patients compared 30 mg daily of a C. sativus extract containing crocin (1.65 to 1.75 mg) with citalopram 40 mg daily for 6 weeks; researchers noted comparable reductions in HAM-D scores throughout the study.43 A pilot study of 30 mg/day of the same C. sativus extract examined effects compared with fluoxetine 40 mg/day in women with postpartum depression; complete response (greater than 50% improvement in HAM-D scores) occurred in 13 patients in the extract group and 16 fluoxetine patients, with remission occurring in 6 and 7 patients, respectively.44

The significant cost of stigma-derived saffron capsules has prompted evaluation of the other plant parts; 2 trials evaluated petal-derived saffron with satisfactory results.34, 37 The Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder (MDD) in adults (2016) recommend saffron as third-line monotherapy or adjunctive therapy for mild to moderate MDD (Level 2).45

Other CNS disorders

Animal data

Studies in rodents have evaluated the effects of aqueous saffron extracts on anxiety, as well as on models of Parkinson disease and dementia.5, 46, 47 A study in mice concluded that the stigma and petal of saffron demonstrated antinociceptive and anti-inflammatory effects.48 In a rat study, crocin 20 and 40 mg/kg demonstrated protection against tardive dyskinesia induced by haloperidol.49

Clinical data

Two small, short-term clinical trials evaluating saffron in Alzheimer disease have been published (N=40, 16 weeks' duration; and N=44, 22 weeks' duration). These studies, conducted by the same group of researchers, reported efficacy with saffron greater than that with placebo and equivalent to that with donepezil.5, 50, 51 One study showed efficacy of saffron in the management of cognitive decline in patients with amnesic and multiple-domain mild cognitive impairment, with improvements in Mini-Mental State Examination scores, while the control group deteriorated (P=0.015).52

Limited clinical studies suggest efficacy in premenstrual syndrome53, 54 and in sexual dysfunction, particularly that related to antidepressant medication.55, 56, 57, 58 However, methodological issues exist in some of the studies,42 and others report no effect for saffron.42, 59 Furthermore, no effects on sperm density, morphology, and motility were reported in limited clinical studies.60, 61

The effects of saffron on satiety were evaluated in an 8-week, placebo-controlled clinical trial in healthy, mildly overweight women (N=60). A reduction in mean snacking frequency was reported; however, no differences in body weight were observed.62, 63

Inflammatory effects

Animal data

Hematological indices (reductions in eosinophil, neutrophil, and lymphocyte counts) and proinflammatory factors in rodents treated with saffron extract suggest anti-inflammatory effects. Antinociceptive and anti-inflammatory activities of saffron and its chemical constituents, as studied in animal experiments, have been reviewed.21, 64

Clinical data

The preventative effects of 10-day saffron supplementation on exercise-induced muscle soreness was compared with indomethacin in a small (N=39) clinical trial. Blinding of participants to treatment is unlikely because the saffron and placebo groups received once-daily dosing, while the indomethacin group adhered to an every-8-hour dosing regimen. Saffron 300 mg once daily decreased biochemical indices (plasma creatine kinase and lactate dehydrogenase) and functional force compared with placebo.65

Ophthalmic effects

Animal data

A review of studies of age-related macular degeneration in animal models has been published;66 the studies suggest that due to its antioxidant and anti-inflammatory effects67, 68 and its ability to increase blood flow,67 saffron may protect against retinal stress.69

Clinical data

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.70, 71 Retinal flicker sensitivity was improved in these studies, suggesting a neuroprotective effect.66

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.72

Other uses

Immunomodulatory effects have been described.73

Properties of saffron as an antidote to chemical toxicities and venom have been reported; the mechanism of action was attributed, in part, to antioxidant activity.17, 18 Reviews of antioxidant action and other properties of saffron and its constituents have also been published.16, 21, 74

Dosing

Clinical studies have evaluated doses ranging from 20 to 400 mg/day of pure saffron.42 A dose-response effect has been suggested.42

Dosages of up to 1.5 g/day of saffron are thought to be safe; toxic effects have been reported for 5 g doses.3, 75

Depression

20 to 30 mg/day of saffron extract (stigma or petal) for mild to moderate depression.5, 75

Hypertension

400 mg/day of saffron tablets for 7 days.29

Pregnancy / Lactation

There is limited evidence of the emmenagogue or abortifacient effects attributed to saffron. In a study among healthy volunteers, saffron 400 mg daily for 7 days caused abnormal uterine bleeding in 2 women.29 A study in the 1960s demonstrated uterine stimulant and estrogenic effects in guinea pigs and mice.29 A high concentration of crocetin was teratogenic in frogs,76 and an aqueous extract of saffron delayed bone ossification in mouse fetuses.77

Avoid use in pregnancy. Amounts higher than those used in food (eg, 5 g or more) have uterine stimulant and abortifacient effects.78, 79

Information regarding safety and efficacy in lactation is lacking.

Interactions

None well documented.78 Conflicting results regarding saffron's effect on human platelets in healthy volunteers were reported, while an aqueous extract of saffron inhibited human platelet aggregation in vitro.27, 29 Therefore, interactions with anti-aggregating drugs are theoretically possible; saffron is contraindicated in bleeding disorders.2

Crocetin binds strongly to serum albumin; however, displacement of plasma-bound drugs has not been evaluated.25, 80

Adverse Reactions

Clinical trials evaluating saffron extract 30 mg daily in the treatment of depression reported no statistically significant adverse events compared with placebo or comparator drugs. Reported adverse effects included nausea, vomiting, and headache.2, 5

In a study of healthy volunteers, saffron 400 mg daily for 7 days caused statistically significant, but not clinically important, increases in serum creatine, sodium, and serum urea nitrogen.29 Similarly, crocin 20 mg in healthy volunteers reportedly produced minor hematological changes but no major adverse effects.81

Allergic reactions are uncommon; however, occupational allergies, including rhinoconjunctivitis, bronchial asthma, and cutaneous pruritus, have been reported.82, 83 Case reports of anaphylaxis also exist.3, 84 Cross-sensitivity has been described among saffron and Lolium, Salsola, and Olea spp.83

Toxicology

A few studies have evaluated the mutagenicity of saffron using the Ames Salmonella test; concentrations of up to 1,500 mcg/plate were found to be nontoxic and nonmutagenic.9, 85

The constituent crocin was not associated with any major toxicity in experimental models,11 except at higher dosages (crocin 100 mg/kg for 2 weeks), in which case hepatotoxicity was observed.81

In clinical trials evaluating dosages of saffron 400 mg, changes in some hematological and biochemical indices were observed. However, no major adverse events occurred.81

Severe adverse effects (including purpura, thrombocytopenia, and severe bleeding) have been reported after ingestion of saffron 5 g.2, 4 A lethal dose is considered to be approximately 20 g; saffron doses of greater than 10 g have been used to induce abortion. Death has been reported with use of saffron as an abortifacient.29 However, saffron is generally not associated with toxicity when ingested in amounts typically used in food.2, 3

References

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A prospective double-blind randomized placebo-controlled study of the effect of saffron (Linn.) on semen parameters and seminal plasma antioxidant capacity in infertile men with idiopathic oligoasthenoteratozoospermia.. 2011;25(4):508-516.2082489461. Heidary M, Vahhabi S, Reza Nejadi J, et al. Effect of saffron on semen parameters of infertile men [published correction appears in. 2009;6(1):71].. 2008;5(4):255-259.1910190062. Gout B, Bourges C, Paineau-Dubreuil S. Satiereal, aL extract, reduces snacking and increases satiety in a randomized placebo-controlled study of mildly overweight, healthy women.. 2010;30(5):305-313.2057952263. Mashmoul M, Azlan A, Khaza'ai H, Yusof BN, Noor SM. Saffron: a natural potent antioxidant as a promising anti-obesity drug.. 2013;2(4):293-308.2678446664. Poma A, Fontecchio G, Carlucci G, Chichiriccò G. Anti-inflammatory properties of drugs from saffron crocus.. 2012;11(1):37-51.2293474765. Meamarbashi A, Rajabi A. 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Functional effect of saffron supplementation and risk genotypes in early age-related macular degeneration: a preliminary report.. 2013;11:228.2406711571. Falsini B, Piccardi M, Minnella A, et al. Influence of saffron supplementation on retinal flicker sensitivity in early age-related macular degeneration.. 2010;51(12):6118-6124.2068874472. Jabbarpoor Bonyadi MH, Yazdani S, Saadat S. The ocular hypotensive effect of saffron extract in primary open angle glaucoma: a pilot study.. 2014;14:399.2531972973. Kianbakht S, Ghazavi A. Immunomodulatory effects of saffron: a randomized double-blind placebo-controlled clinical trial.. 2011;25(12):1801-1805.2148041274. Khorasany AR, Hosseinzadeh H. Therapeutic effects of saffron (L.) in digestive disorders: a review.. 2016;19(5):455-469.2740325175. Lopresti AL, Drummond PD. Saffron () for depression: a systematic review of clinical studies and examination of underlying antidepressant mechanisms of action.. 2014;29(6):517-527.2538467276. Martin G, Goh E, Neff AW. Evaluation of the developmental toxicity of crocetin on Xenopus.. 2002;40(7):959-964.1206521877. Golalipour MJ, Gharravi AM, Ghafari S, Afshar M, Khori V. Effects ofon the fetal development of NMRI mice.. 2008;29(2):309-310.1824625178. Brinker FJ.. 2nd ed. Sandy, OR: Eclectic Medical Publications; 1998.79. Ernst E. Herbal medicinal products during pregnancy: are they safe?. 2002;109(3):227-235.1195017680. Miller TL, Willett SL, Moss ME, Miller J, Belinka BA Jr. Binding of crocetin to plasma albumin.. 1982;71(2):173-177.706223981. Alavizadeh SH, Hosseinzadeh H. Bioactivity assessment and toxicity of crocin: a comprehensive review.. 2014;64:65-80.2427509082. Martínez FV, Muñoz Pamplona MP, Urzaiz AG, García EC. Occupational airborne contact dermatitis from saffron bulbs.. 2007;57(4):284-285.1786823183. Feo F, Martinez J, Martinez A, et al. Occupational allergy in saffron workers.. 1997;52(6):633-641.922605784. Wüthrich B, Schmid-Grendelmeyer P, Lundberg M. 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