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Crocus sativus L. belonging to the family Iridaceae (syn - kesar) comprises the dried red stigma and is widely cultivated in Greece. 

Saffron contains more than 150 volatile and aroma-yielding compounds mainly terpenes, terpene alcohol, and their esters. 

The bitter taste and an iodoform or hay-like fragrance are caused by chemicals picrocrocin and safranal. C. sativuspossesses a number of medicinally important activities such as antihypertensive, anticonvulsant, antitussive, antigenototoxic and cytotoxic effects, anxiolytic aphrodisiac, antioxidant, antidepressant, antinociceptive , anti-inflammatory, and relaxant activity. It also improves memory and learning skills, and increases blood flow in retina and choroid. 

The present review explores the historical background, chemical constituents, pharmacological actions, uses, substitutes and adulterants, and toxicity. It also deals with its evaluation, formulations, and chemical tests in detail.

Commercial saffron comprises the dried red stigma with a small portion of the yellowish style attached.[1

 A definite identification of saffron crocuses dates from about 1700-1600 BC, in the form of a fresco painting in the Palace of Minos at Knossos in Crete. The wild precursor of domesticated saffron crocus was Crocus cartwrightianus

Experts believe saffron was first documented in a 7th centaury BC Assyrian botanical reference compiled under Ashurbanipal. Since then, documentation of saffron's use over the span of 4000 years in the treatment of some 90 illnesses has been uncovered. It is in leaf from October to May, and in flower in October

The flowers are hermaphrodite (have both male and female organs) and are pollinated by bees and butterflies. The plant prefers light (sandy) and medium (loamy) soils, requires well-drained soil, and can grow in nutritionally poor soil. The flower has three stigmas, which are the distal ends of the plant's carpels. Together with the style, the stalk connecting the stigmas to the rest of the plant are often dried and used in cooking as a seasoning and coloring agent. Saffron blooms only once a year and should be collected within a very short duration. It is picked during 3-4 weeks in October-November.

The method for the cultivation of saffron contributes greatly to its high price. According to some reports, this species is a sterile triploid and so does not produce fertile seeds. Germination can take 1-6 months at 18°C.[15] It takes 3 years for plants to flower from seed.[36] Saffron is characterized by a bitter taste and an iodoform or hay-like fragrance, which are caused by chemicals picrocrocin and safranal.[7] The value of saffron (stigmas of C. sativus L.) is determined by the existence of three main secondary metabolites: crocin, picrocrocin, and safranal.[8,9] Saffron is used for depression in Persian traditional medicine.[1013] Pistils of saffron are generally used in traditional Indian medicine as analgesics and cardio-protective agents, as well as in the treatment of various kinds of mental illnesses. A crude extract of pistils of saffron improves recovery in ischemia/reperfusion injury and learning and memory in rats. In traditional medicines, saffron is recommended as an aphrodisiac agent.[14]

Antihypertensive activity

Fatehi and others investigated the effects of C. sativus petals’ extract on blood pressure in anesthetized rats and also on responses of the isolated rat vas deferens and guinea -pig ileum induced by electrical field stimulation (EFS). Aqueous and ethanol extracts of C. sativus petals’ reduced the blood pressure in a dose-dependent manner. Administration of 50 mg/g of aqueous extract changed the blood pressure from 133.5 ± 3.9 to 117 ± 2.1 (mmHg). This reduction could either be due to the effect of the C. sativuspetals’ extracts on the heart itself/total peripheral resistance, or both. The effect of extracts on peripheral resistance seems to be more important.[23] In the rat isolated vas deferens, contractile responses to EFS were decreased by the petals’ extracts. Contractions of the vas deferens to EFS are mediated by a combination of noradrenaline and ATP released as cotransmitters from sympathetic nerves.[24] The ethanol extract induced greater changes in EFS in the rat isolated vas deferens and guinea- pig ileum than the aqueous extract.[23]

Antitussive activity

The antitussive activity of C. sativus stigma and petal extracts and its components, safranal and crocin, was evaluated using the nebolized solution of citric acid 20% in guinea pigs. The ethanolic extract of C. sativus (100-800 mg/kg) and safranal (0.25-0.75 ml/kg) reduced the number of cough. The ethanolic and aqueous extracts of petal and crocin did not show antitussive activity.[26]

Antigenototoxic and cytotoxic effects of saffron

The antimutagenic, comutagenic, and cytotoxic effects were assessed using the Ames/Salmonella test system, two well-known mutagen (BP, 2AA), the in vitro colony-forming assay, and four different cultured human normal (CCD-18LU) and malignant (Hela,a-204 and Hepg2) cells. When only using the TA98 strain in the Ames/Salmonella test system, saffron showed nonmutagenic, as well as non-antimutagenic activity against BP-induced mutagenicity and demonstrated a dose-dependent co-mutagenic effect on 2-AA-induced antimutagenicity. The saffron component responsible for this unusual co-mutagenic effect was safranal. In the in vitro colony-forming test system, saffron displayed a dose-dependent inhibitory effect only against human malignant cells. All isolated carotenoid ingredients of saffron demonstrated cytotoxic activity against in vitro tumor cells. Saffron crocin derivatives possessed a stronger inhibitory effect on tumor cell colony formation. Overall, these results suggest that saffron itself, as well as its carotenoid components, might be used as potential cancer chemopreventive agents.[27]

Effect on sexual behavior

The aphrodisiac activities of C. sativus stigma aqueous extract and its constituents, safranal and crocin, were evaluated in male rats. The aqueous extract (80, 160, and 320 mg/kg body wt.), crocin (100, 200, and 400 mg/kg body wt.), safranal (0.1, 0.2, and 0.4 ml/kg), sildenafil (60 mg/kg body wt., as a positive control), and saline were administered intraperitoneally to male rats. Mounting frequency (MF), mount latency (ML), intromission latency (IL), and ejaculation latency (EL) were the factors evaluated during the sexual behavior study. Crocin, at all doses, and the extract, especially at doses 160 and 320 mg/kg body wt., increased MF, IF, and EF behaviors and reduced EL, IL, and ML parameters. Safranal did not show aphrodisiac effects. This study exhibited an aphrodisiac activity of saffron aqueous extract and its constituent crocin.[28]

Anxiolytic activity

This study was designed to investigate in rodents whether or not crocins possess anxiolytic properties. For this aim, the light\dark test was selected. Either crocins, at a dose which did not influence animals’ motor activity (50 mg/kg), or diazepam (1.5 mg/kg), increased the latency to enter the dark compartment and prolonged the time spent in the lit chamber in the rats. Conversely, lower doses of crocins (15-30 mg/kg) did not substantially modify animals’ behavior. The present results indicate that treatment with these active constituents of C. sativus L. induces anxiolytic-like effects in the rat.[29]

Relaxant property

To study the mechanism(s) of the relaxant effects of C. sativus (Iridaceae), the stimulatory effect of aqueous-ethanolic extracts of this plant and one of its constituent, safranal, was examined on β-adrenoreceptors in tracheal chains of guinea pigs. The β2-adrenergic stimulatory was tested by performing the cumulative concentration-response curves of isoprenaline-induced relaxation of pre-contracted isolated guinea pig tracheal chains. The studied solutions included two concentrations of aqueous ethanolic extracts from C. sativus (0.1 and 0.2 g%), safranal (1.25 and 2.5 μg), 10 nM propranalol, and saline. The study was done in two different conditions including non-incubated (group 1, n = 9) and incubated tissues with 1 μM chlorpheniramine (group 2, n = 6). The results showed clear leftward shifts in isoprenaline curves obtained in the presence of only higher concentration of the extract in group 1 and its both concentrations in group 2 compared with that of saline. The EC50 (the effective concentration of isoprenaline, causing 50% of maximum response) obtained in the presence of both concentrations of the extract (0.17 ± 0.06 and 0.12 ± 0.02) and safranal (0.22 ± 0.05 and 0.22 ± 0.05) in group 1 and only in the presence of two concentrations of the extract (1.16 ± 0.31 and 0.68 ± 0.21) in group two was significantly lower compared to saline. The maximum responses obtained in the presence of both concentrations of the extract and safranal in group 1 were significantly lower than that of saline. The results indicated a relatively potent stimulatory effect of the extract from C. sativus on β2-adrenoreceptors, which is partially due to its constituent, safranal. A possible inhibitory effect of the plant on histamine (H1) receptors was also suggested.[30]

Effect on depression

The efficacy of petal of C. sativus was assessed in the treatment of mild-to-moderate depression in a 6-week double-blind, placebo-controlled and randomized trial. Forty adult outpatients who met the Diagnostic and Statistical Manual (DSM) of Mental Disorders, fourth edition for major depression based on the structural clinical interview for DSM IV, participated in the trial. In this double-blind, placebo-controlled and randomized trial, patients were randomly assigned to receive capsule of petal of C. sativus30 mg/day (b.d.) (Group 1) and capsule of placebo (b.d.) (Group 2) for a 6-week study. At 6 weeks, petal of C. sativus produced a significantly better outcome on Hamilton Depression Rating Scale than placebo (d.f. = 1, F = 16.87, P<0.001). There were no significant differences in the two groups in terms of observed side-effects. The results of this study indicate the efficacy of petal of C. sativus in the treatment of mild-to-moderate depression.[31] In further preliminary work, saffron was compared to the drug fluoxetine; it was found that the saffron performed as well as the drug in the treatment of depression.[13] In addition, in a recent pre-clinical study, it has been reported that petal of C. sativus, the part of this herb that is very cheap compared to stigma of C. sativus (saffron), has antidepressant effect.[11]

Effect on learning behavior and long-term potentiation

The saffron extract and two of its main ingredients, crocin and crocetin, improved memory and learning skills in ethanol-induced learning behavior impairments in mice and rats. Oral administration of saffron may be useful in the treatment of neurodegenerative disorders and related memory impairment.[8,32]

Effects on ocular blood flow and retinal function

Crocin analogs isolated from saffron significantly increased the blood flow in the retina and choroid as well as facilitated retinal function recovery and it could be used to treat ischemic retinopathy and/or age-related macular degeneration.[33]

Effect on coronary artery disease

Fifty milligrams of saffron dissolved in 100 ml of milk was administered twice a day to human subjects, and the significant decrease in lipoprotein oxidation susceptibility in patients with coronary artery disease (CAD) indicates the potential of saffron as an antioxidant.[34]

Antinociceptive and anti-inflammatory effects

Saffron stigma and petal extracts exhibited antinociceptive effects in chemically induced pain test as well as acute and/or chronic anti-inflammatory activity, and these effects might be due to the presence of flavonoids, tannins, anthocyanins, alkaloids, and saponins.[10]