Saffron

January 2010

Crocus sativus L. Family: Iridaceae

Saffron , za'faran

Uses

Saffron has widespread traditional uses. It has demonstrated efficacy in mild to moderate depression; however, a limited number of quality clinical trials exist. Potential exists for a role in the treatment of cancer and age-related macular degeneration.

Dosing

Clinical trials are lacking to guide dosage of saffron. A dosage of 30 mg daily in 2 divided doses has been investigated for the treatment of mild to moderate depression and in premenstrual syndrome. Doses of up to 1.5 g/day of saffron are thought to be safe; toxic effects have been reported at 5 g.

Contraindications

Contraindications have not yet been identified. High doses should be avoided in pregnancy.

Pregnancy/Lactation

Avoid use. Amounts of more than 5 g, which is greater than amounts used in food, have uterine stimulant and abortifacient effects. There is no information regarding use in lactation.

Interactions

None well documented. Interaction with platelet antiaggregating drugs is theoretically possible. Crocetin binds strongly to serum albumin.

Adverse Reactions

Clinical trials evaluating saffron in depression at dosages of 30 mg daily reported no statistically significant adverse events versus either placebo or comparator drugs. Reported adverse effects include nausea, vomiting, and headache. Death has resulted from the ingestion of doses of more than 10 g. Allergic reactions are uncommon; however, occupational allergy, including rhinoconjunctivitis, bronchial asthma, and cutaneous pruritus, has been reported. Case reports of anaphylaxis exist.

Toxicology

Information is limited.

True saffron is native to Asia Minor (Anatolia) and southern Europe, with the majority of the world production based in Iran. Its blue-violet, lily-shaped flowers contain the orange stigmas (part of the pistil) and red style branches that are collected to produce the saffron spice. The plant is a bulbous perennial and grows 15 to 20 cm in height. Mature stigmas are collected by hand during a short blooming season. Over 200,000 dried stigmas, obtained from about 70,000 flowers, yield 0.5 kg of true saffron. Saffron may cost as much as $30 per ounce in the American market.

True saffron should not be confused with Carthamus tinctorius L. (family Asteraceae), also called American saffron (safflower, Indian safflower), that is produced from the tubular florets and is a lighter red than true saffron. The two are often used for the same purposes, and the less expensive American saffron is sometimes used to adulterate true saffron. ^1, , ^2, , ^3, , ^4, , ⁵

Saffron use has been traced to ancient Egyptian and Roman times when it was first used for medicinal value, and only later becoming valued as a spice and dye. The word saffron is thought to originate from the Arabic za'faran , meaning yellow. Folkloric uses of saffron have included its use as a sedative, expectorant, aphrodisiac, emmenagogue, and diaphoretic. During the 16th through 19th centuries, saffron was used in various opioid preparations, including laudanum and “black-drop” for pain relief.

Saffron has been used for a wide variety of ailments, including cramps, asthma, menstrual disorders, in liver disease, for pain and as an antidepressant and aphrodisiac. In the Indian Ayurvedic health system it is considered an adaptogen. However, the Complete German Commission E Monographs negatively evaluated saffron for use in cramps or asthma. United States patents were issued in the 1970s for the proposed use of crocetin in the treatment of skin papillomas, spinal cord injuries, hypertension, and cerebral edema in cats. Various patents exist for saffron in combination with other agents. ^3, , ^4, , ^6, , ^7, , ⁸

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. ^3, , ^9, , ^10, , ^11, The major carotenoid derivatives crocetin, picrocrocin, and safranal are found in saffron. The characteristic taste of the spice is attributed to the glycoside picrocrocin, while safranal is considered to be the main odiferous constituent achieved through hydrolysis of picrocrocin. ^3, , ^12, , ¹³

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. ¹³ 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 has been published. ¹²

Cancer Saffron appears to be selectively cytotoxic by mechanisms not fully understood, ^3, , ^14, , ^15, , ^16, inhibiting proliferation and disease progression while healthy cells remain viable. ^3, , ^4, , ^10, , ^17, , ^18, , ^19, Effects are shown to be concentration- and time-dependent. ^3, , ^20, The toxicity of cytostatic drugs, such as cisplatin, is reduced with concurrent administration of saffron extracts without affecting the drugs' antitumor activity. ^3, , ^4, , ^21, The lifespan of animals with induced carcinomas was increased with the administration of saffron extracts. ^22, , ^23, , ²⁴

Reviews of the potential role of saffron extracts in cancer therapy have been published. Although promising, data is limited to in vitro and animal experimentation; clinical trials are lacking. ^3, , ^4, , ²⁵

Cardiovascular effects Clinical trials are limited. Epidemiologic evidence suggests that the low incidence of cardiovascular disease in parts of Spain may be related to the liberal, almost daily consumption of saffron. Algae in Japanese diets that also contain crocetin may have a similar protective effect. ²⁶

Studies in animals have shown that aqueous and ethanolic saffron extracts reduce blood pressure in a dose-dependent manner. ^3, 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 mean arterial pressure. ²⁷

Rabbits with induced hyperlipidemia showed decreased cholesterol and triglyceride levels and reduced vascular damage when treated with crocetin. Hypoxia at the vascular wall was also reduced. ^28, , ^29, However, in a study of healthy volunteers, saffron 400 mg daily for 7 days had no effect on the lipid profile. ²⁷

Crocetin produced an 80% increase in the oxygen diffusivity of plasma ^29, and binds strongly to serum albumin. ^11, , ^30, An antioxidant effect was demonstrated in human platelets with the inhibition of lipid peroxidation, ^11, , ^31, , ^32, while improved antioxidant status was shown in patients with coronary artery disease given saffron 50 mg extract twice daily. ^3, , ⁴

Depression A number of well-designed clinical trials have been conducted evaluating the efficacy of saffron 30 mg daily over 6 to 8 weeks in mild to moderate depression. ^33, , ^34, , ^35, , ^36, , ^37, The studies found saffron to be more effective than placebo and at least equivalent to therapeutic doses of imipramine and fluoxetine using the Hamilton Depression Rating Scale. No significant differences were found in adverse events in any of the studies. However, the studies involved small sample sizes (40 patients) and were conducted by the same group of researchers, within a non–Western population. ^38, , ^39, The cost of stigma-based saffron capsules is significant, and 2 of the trials evaluated petal-derived saffron with satisfactory results. ^33, , ^36, The same researchers favorably evaluated saffron for the relief of premenstrual syndrome. ⁴⁰

Ophthalmic In vitro experiments demonstrated a concentration-dependent protective effect of the carotenoid crocin and its analogs on animal retina. ^41, , ^42, Increased blood flow in the retina and choroid has been demonstrated. ^41, As a dietary supplement, saffron extract prevented retinal damage in rats, ^43, and it may have a role in the treatment of ischemic retinopathy and age-related macular degeneration. ³

Other uses Ethanol-impaired memory was improved in mice treated with crocin, but not crocetin, and it may have a direct effect on the hippocampus. ^44, Other trials have been conducted in animals to evaluate the effect of saffron on learning behavior, memory, and neuronal cell death. ³

A study in mice concluded that the stigma and petal from saffron demonstrated antinociceptive and anti-inflammatory effects. ⁴⁵

Saffron tea has been used in the management of psoriasis. ⁴⁶

Saffron combined with hematoxylin-eosin or hematoxylin-phyloxin is used as a staining method in various procedures (ie, examining giant cell tumors, cell death, and airway smooth muscle orientation). ^47, , ^48, , ⁴⁹

Clinical trials are lacking to guide dosages of saffron.

A dosage of 30 mg daily in 2 divided doses has been evaluated for the treatment of mild to moderate depression, and in premenstrual syndrome. ^33, , ^34, , ^35, , ^36, , ³⁷

Improved antioxidant status was shown in patients with coronary artery disease given saffron 50 mg extract twice daily in an older trial. ^3, , ⁴

Doses of up to saffron 1.5 g daily are thought to be safe; toxic effects have been reported for 5 g dosages. ⁴

There is limited evidence to support 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. ^27, A study in the 1960s demonstrated uterine stimulant and estrogenic effects in guinea pigs and mice. ^27, A high concentration of crocetin was teratogenic in frogs, ^50, and an aqueous extract of saffron delayed bone ossification in mouse fetuses. ⁵¹

Amounts of more than 5 g are higher than the amounts used in food and may have uterine stimulant and abortifacient effects. ^52, , ⁵³ Avoid use.

Information regarding use in lactation is unavailable. Avoid use.

None well documented. ^52, Conflicting results of saffron's effect on platelets were observed among healthy volunteers, while an aqueous extract of saffron inhibited human platelet aggregation in vitro. ^27, , ³² Interactions with antiaggregating drugs is, thus, theoretically possible.

Crocetin binds strongly to serum albumin; however, displacement of plasma-bound drugs has not been evaluated. ^11, , ³⁰

Clinical trials evaluating dosages of saffron 30 mg daily in depression reported no statistically significant adverse events versus either placebo or comparator drugs. Reported adverse effects include nausea, vomiting, and headache. ^3, , ⁴

In a study among 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. ²⁷

Allergic reactions are uncommon; however, occupational allergy, including rhino-conjunctivitis, bronchial asthma, and cutaneous pruritus, has been reported. ^54, , ^55, Case reports of anaphylaxis exist. ^4, , ⁵⁶ Cross-sensitivity has been described among saffron and Lolium , Salsola , and Olea species. ⁵⁵

Fatalities occurring from the use of saffron as an abortifacient have been cited. ²⁷

The following effects were reported after ingestion of saffron 5 g: severe purpura, thrombocytopenia, and severe bleeding. ^6, A lethal dose is considered to be 20 g and an abortifacient at 10 g. Nevertheless, saffron is generally not associated with toxicity when ingested in culinary amounts. ⁴

The median lethal dose has been estimated at 20.7 g/kg as a decoction in animal studies, ^29, and saffron extract 600 mg/kg body weight for mice. ⁴

A few studies have evaluated the mutagenicity of saffron using the Ames/Salmonella test; concentrations of up to 1,500 mcg/plate have been found nontoxic and nonmutagenic. ^3, , ²⁵

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