Saffron

Crocus sativus (of the family iridaceae) is a spice commonly referred to as saffron, which is derived from the arabic word za-faran meaning "be yellow"^[1] and a previous name for it (pre-Grecian) was Krokos.^[2] Saffron's history is mostly culinary where it was a prized spice, and the medicinal uses were limited although ancient Romans attempted to prevent hangovers by putting saffron in their wine,^[2] and it has been reported to have anxiolytic and sedative uses^[3] while also being used as an antidepressive agent in traditional Persian medicine.^[4]

Saffron is a traditionally used spice, and does not have an extensive historical use for medicine. Most historical usage is culinary, to flavor fish and seafood dishes.

Saffron is mostly produced in Iran, where it accounts for up to 90% of the world's supply^[5] although spanish saffron (the former world leader in production) is reported to be of higher culinary quality.^[2]

Its production is usually labour intensive, with saffron production thought to total 190kg annually and anywhere between 150,000-200,000 flowers and 400 hours of labor to produce 1kg of dried stigma (the main component of the spice used), due in part to only three stigma existing in one plant and each weighing only 2mg.^[6][7] The petals of saffron are a byproduct of production, despite being much more plentiful and accounted to about 10,000 tonnes annually.^[1] This labour-intensive process mostly explains why saffron is currently the world's most expensive spice.^[2]

Saffron js very expensive because harvesting adequate amounts of the stigma (the main culinary and supplemental part of the plant) is very labor-intensive, and because the labour produces a low yield of stigma.

Saffron stigma contains:

• Picrocrocin (hydroxysafranal β-D-glucoside) which is the main bitter component of saffron^[8] as well as picrocrocin acid form^[9]
• Safranol and hydroxysafranol, which are monoterpene aldehydes which result in the characteristic aroma and taste of saffron^[10] and are lysed from the picrocrocin molecule after heat treatment
• Crocin molecules, which are water soluble carotenoids.^[11] These are divided into Crocin 1 (17.823mg/g of the water extract^[11]), Crocin 2 (trans-crocin-2, cis-crocin-2, and trans-crocin-2';^[11] the former being 7% of the total carotenoids^[9]), Crocin 3 (trans-crocin-3 and cis-crocin-3, with the former at 26% total carotenoids^[9]), Crocin-4 (trans-crocin-4 and cis-crocin-4, with the former amounting to 46% total carotenoids and the latter 12%^[9]) and Crocin 5 (cis-crocin-5^[9])
• Zeaxanthin, a fat soluble carotenoid^[12]

Saffron components can be divided into either small aromatic aldehydes (safranal and its glycoside, known as picrocrocin) and the carotenoids, known as crocins, which have varying forms depending on the sugars bound to them.

Saffron crom tends to contain:

• n-tridecane^[11]
• n-tetradecane^[11]
• n-pentadecane^[11]
• n-heptadecane^[11]
• diethyltoluamide^[11]
• n-catane^[11]
• Hexadecanoic acid^[11]
• Octadecadienoic acid^[11]
• Dietary minerals such as magnesium (665-680µg/g^[13]), manganese (4.8-6.1µg/g^[13]), calcium (2,868-3,110µg/g^[13]), zinc (16.2-18.3µg/g^[13]), and potassium (4,395-4,870µg/g^[13])

The term 'crocin' tends to refer to the basic carotenoid structure in saffron, which are atypically water soluble (majority of carotenoids such as astaxanthin or β-carotene being fat soluble). Different variations of crocin (ie. crocin-4 or crocin-1) refer to different sugar molecules added to each end of the molecule.

Processing of saffron (after growing) requires a drying phase, with a few methods (sun drying, toasting, or putting the stigma into a dark and temperature-controlled room) being used, all with the goal of reducing the moisture content to 10-12%;^[10][14] the goal of heat treatment also being to cause picrocrocin to release safranal for the aroma.^[15] Variations in processing are mostly of concern for the aromatic properties of saffron, as both low temperature (less than 30°C) with long duration as well as the inverse (over 60°C) reduce quality of saffron by increasing degradation of the pigmentation (crocins).^[14]

Processing of saffron tends to free up safranal and reduce picrocrocin, which results in a more desirable taste and aromatic properties.

Crocins in saffron are thought to hinder 5-HT_2C signalling due to antagonizing the effects of m-Chlorophenylpiperazine (mCPP), a serotonin receptor agonist,^[16] in a rat model.^[17]

In vivo evidence in rat models suggests that the crocins found in saffron have serotonergic effects.

Intraperitoneal injections of saffron extracts from both the stigma and petal (360-1,400mg/kg) have shown analgesic properties in an acetic acid writhing test, in a manner partially blocked by naxolone (an opioid antagonist), without any effects in a hot plate test in mice, which may suggest that the extract acts as an analgesic non-centrally. ^[18]

High doses of saffron may have analgesic properties in rats, although the dosage used and method of administration (injections) makes it questionable whether these results would occur with oral ingestion of saffron.

Supplementation of saffron stigma (176.5mg daily) in overweight women without eating disorders and not on a controlled diet resulted in less snacking with saffron (55% reduction) than with placebo (28%) combined with less reported hunger after eight weeks;^[19] this was thought to underlie a modest reduction in body weight (0.96+/-0.26kg).^[19]

One study on overweight women has noted a reduction in snacking frequency and subjective hunger associated with moderate weight loss.

In the rat, crocins at an oral dose of 30 and 50mg/kg have failed to alter locomotor activity^[17] whereas intraperitoneal administration of higher doses (up to 600mg/kg) of crocin in mice can reduce locomotor activity to a small degree^[3] and 50mg/kg injections have been implicated in both a minor reduction in motor activity^[3] or no significant changes.^[20]

Standard doses of saffron in rodents do not appear to be associated with sedation, although higher injected doses appear to induce sleepiness. Currently there is no human evidence investigating this property of saffron.

Injections of saffron water extract (56-80mg/kg) appears to have anxiolytic properties in mice while higher doses up to 560mg/kg lose their efficacy, and isolated crocins (50-600mg/kg) do not appear to be effective.^[3] The potency of the water extract in the open field test and elevated plus maze appears to be comparable to 3mg/kg diazepam.^[3] This anxiolytic effect has been noted elsewhere with isolated crocins at 50mg/kg, although lower doses (15-30mg/kg) were ineffective.^[20]

The crocins of saffron appear to have anxiolytic propeties in mice at moderate, but not lower, doses. No studies exist on humans investigating oral supplementation of saffron.

In humans, one study attempting aromatherapy in a double blind manner (ethanol as placebo, saffron diluted in ethanol below the detectable limit for experimental) noted that 20 minutes exposure to the aroma of saffron was sufficient to cause a mild (approximately 10%) reduction of anxiety as assessed by the STAI.^[21]

One study has noted that the aroma of saffron resulted in minor reductions in anxiety, suggesting relaxing properties via aromatherapy.

Oral ingestion of 150-600mg/kg of crude saffron extract in rats reduced depressive symptoms in a dose-dependent manner with the highest dose being comparable to 100mg/kg fluoxetine.^[11] Most efficacy being seen in the petroleum ether and dichloromethane extracts of the corm or the water extract of the stigma, although the major components in the corm (Octadecadienoic and Hexadecanoic acids) differed from that of the stigma (crocins).^[11]

Saffron appears to have antidepressant properties secondary to the crocin content, as safranal appears to be mostly inactive.

A meta-analysis on the usage of saffron on depressive symptoms^[5] (against either placebo or antidepressant reference drugs) found that the usage of saffron supplementation in five trials at 30mg noted that saffron was more effective than placebo in two studies^[4][22] although the studies comparing it to reference drugs (imiprazole and fluoxetine) failed to find a significant difference in efficacy although saffron appeared to be associated with less side-effects.^[23][24][25]

At least one study has investigated the petals of saffron rather than the stigma (flowers being an industrial byproduct) and over eight weeks in depressive people given 15mg saffron petal extract twice daily (300-350µg safranal per capsule) performed equally to fluoxetine 10mg twice daily.^[23] Both treatments caused a time-dependent reduction in depressive symptoms on the HAM-D rating scale and s similar amount of people reached a 50% reduction in depressive symptoms (75-85%) and remission (25%).^[23]

The petals of saffron, perhaps a cheaper option due to being an industrial byproduct not used in spice making, also appear to be effective for the treatment of depression, with a potency comparable to reference drugs.

Two studies, one in men and one in women, have found that saffron as an ajuvant to fluoxetine may alleviate the sexual dysfunction related to floxetine treatment while having no additional effects on its antidepressive action.^[26][27]

When used as an adjuvant for SSRI (fluoxetine) therapy, saffron neither hinders nor augments the antidepressive effects of fluoxetine, despite counteracting floxetine-induced sexual dysfunction.

One study assessing the safety of saffron supplementation in the 200-400mg dosage range noted that, following a week of supplementation, 40% of subjects taking the higher dose of saffron reported elevations in mood.^[28]

One study noted that saffron elevated mood in healthy people.

Crocins from saffron could be beneficial for OCD, as crocins are able to reverse a chemically-induced model of OCD in rats.^[17] In this study, rats undergoing chemically-induced OCD after being administered mCPP had their symptoms reduced by approximately half when given 30 and 50mg/kg crocins, although symptoms remained higher than that of controls not given mCPP;^[17] crocins failed to prevent the reduction in locomotor behaviour of the rats given mCPP.^[17]

Saffron may affect the symptoms of obsessive compulsive disorder, but there is no human evidence that this is the case, and the rodent evidence is sparse.

50mg of saffron stigma dissolved in milk and given twice daily for six weeks appears to cause a time-dependent reduction in the susceptability of LDL to oxidation in both healthy controls and persons with coronary artery disease.^[29]

One study has noted a reduction in LDL oxidation susceptability, although further testing is needed, as the lone study was small and not placebo controlled.

Due to its potential anti-inflammatory properties, saffron has been investigated in humans for the prevention of delayed-onset muscle soreness (DOMS). Over 10 days, 39 non-active college students took either 300 mg dried saffron, 75 mg (25 mg thrice daily) indomethacin (an NSAID), or placebo. The saffron group maintained the maximum isotonic and isometric force they could exert 24-72 hours after the exercise, while the placebo group's performance was reduced, and the saffron group outperformed the indomethacin group 72 hours after the exercises. Plasma creatine kinase and lactate dehydrogenase levels (indicators of muscle damage) were also reduced in the saffron group compared to placebo at 24-72 hours; the indomethacin group was similar at 48-72 hours after exercise, but was more similar to placebo at 24 hours. Perceived pain in the saffron group was also similar to indomethacin; both groups had an average pain perception close to 0 on a 6-point scale after 48 and 72 hours, while the placebo group had a rating of around 3 to 4. At 24 hours after exercise, saffron outperformed indomethacin; the saffron group had a perceived pain rating of about 0.5, whereas the indomethacin group had a rating of about 1.5.^[30]

One human study suggests that 300 mg saffron may reduce DOMS from eccentric exercise in untrained individuals.

Supplementation of 100mg saffron extract (crude powder of the stigma) in healthy men once daily for three weeks increased serum IgG concentrations (24.2%) while reducing IgM concentrations (42.5%), although these differences were normalized after an additional three weeks; IgA was unaffected at all times.^[31]

Higher-than-normal doses of saffron have been noted to temporarily alter immunoglobulin concentrations in the serum of healthy men, with lower doses not yet tested.

Following oral ingestion of 100mg crude saffron extract (stigma), monocyte concentrations increased (9%) after three weeks alongside changes in immunoglobulins while the change was not detectable after six weeks.^[31]

Total lymphocytes (including T and B cells) are not affected following supplementation of 100mg crude saffron extract in otherwise healthy men over six weeks relative to placebo.^[31]

Following oral ingestion of 100mg crude saffron extract (stigma), basophil concentrations decreased (20%) after three weeks alongside changes in immunoglobulins while the change was not detectable after six weeks.^[31]

Saffron as aromatherapy (20 minutes of exposure) in otherwise healthy women appears to cause a mild increase in estradiol concentrations in saliva in both the luteal and follicular phases relative to baseline.^[21]

Aromatherapy of saffron has resulted in an acute increase in estrogen in otherwise healthy women; prolonged oral supplementation has not been tested and the practical significance of this information is not yet known.

Saffron as aromatherapy (20 minutes of exposure) in otherwise healthy women does not appear to significantly influence testosterone concentrations^[21] and supplementation of saffron at 60mg (30mg twice daily) over the course of 26 weeks in infertile men has failed to modify circulating testosterone concentrations relative to placebo.^[32]

Both oral supplementation in men as well as aromatherapy in women have failed to significantly influence testosterone concentrations.

Saffron as aromatherapy (20 minutes of exposure) in otherwise healthy women appears to cause a reduction in cortisol from approximately 1.6µg/dL to 1.0µg/dL (luteal phase) and from 0.135µg/dL to 0.09µg/dL (follicular phase).^[21] This reduction in cortisol occurred alongside a mild reduction in state anxiety as assessed by STAI.^[21]

Aromatherapy of saffron has been implicated in reducing cortisol mildly in otherwise healthy women.

Crocetin appears to be able to bind to DNA and form adducts in various cancerous lines (HeLa, A-549, and VA-13)in vitro ^[33] while crocetin and other compounds derived from saffron (dihydrocrocetin and safranal) also have this property in normal cells,^[34] with the binding constants in normal cells being in the range of 18.5µM (dihydrocrocetin) to 1.24mM (safranal).^[34] Crocetin is thought to act in the nucleus, since it exhibits similar potency in inhibiting DNA and RNA synthesis in whole cells as in isolated nuclei.^[33]

Crocetin in saffron appears to associate with DNA, and while this is speculated to act in an antioxidative manner when bound to DNA, its exact role is not yet ascertained.

When assessing the UV radiation protective effects of saffron, a cream containing 4% dried and powdered saffron appears to have a similar sun protection factor (SPF) as an 8% homosalate solution (as reference drug) in vitro whereas an 8% saffron cream outperformed homosalate.^[35]

Topical application of a cream containing 2-8% saffron to volunteers does not appear to modify moisture content of the skin after seven hours following a single administration.^[35]

Topical application of saffron-containing cream may have solar protective (sunscreen) properties with a potency comparable to or greater than an agent commonly used in sunscreens (homosalate).

One study assessing the effects of saffron on PMS symptoms noted time-dependent benefits of 30mg saffron taken daily over the course of two menstrual cycles, where at the end of the second cycle 76% of women reported over a halving of total symptoms (versus 8% in placebo).^[36] Depressive symptoms as assessed by the HAM-D were reduced by over half in 60% of women taking saffron, while only 4% of women taking placebo achieved this.^[36] The only other study on the topic which used saffron also used fennel and celery seed concurrently, so conclusions regarding the effects of saffron alone cannot be deduced from this study.^[37]

Saffron has been tested for its ability to prevent or attenuate SSRI-related sexual dysfunction, in part due to its ability to increase measures of libido in male rats, a property traced back to saffron's crocin content, but not its safranal content.^[38]

In women who benefitted from SSRI therapy for depression but reported sexual dysfunction, supplementation of 15mg saffron stigma extract twice daily (3.3-3.5mg crocin daily) had statistically significant improvements on the self-reported Female Sexual Function Index (FSFI) in the subscales of arousal, lubrication, pain, but not in desire, sexual satisfaction, or orgasm after 4 weeks of supplementation.^[26] Similar effects were seen in men with major depressive disorder stabilized on SSRI therapy, where supplementation of the same dose of saffron for four weeks improved erectile function and satisfaction with intercourse but not sexual desire, orgasm, and overall sexual satisfaction.^[27]

A small pilot study investigating the effects of saffron on men with erectile dysfunction found benefits with supplementation for 10 days with a high dose of saffron (200mg daily)^[39] although a later and larger study also assessing erectile dysfunction in men using 15mg of the petal extract twice daily for four weeks failed to note any improvement on the same rating scale (IIEF) or other self-reported measures of erectile function.^[40] This study noted that the majority of cases of erectile dysfunction (72.2%) were vascular in nature, with lower amounts being traced back to neurogenic (3.5%) or psychogenic (24.3%) causes.

Saffron has been noted to improve parameters of sexual function in both men and women experiencing sexual dysfunction from SSRI therapy, although the one larger study in men with general erectile dysfunction did not find any improvements.

One uncontrolled study assessing the effects of saffron on male seminal parameters noted that, when given 50mg of saffron in milk thrice a week, seminal motility and morphology improved without any alterations in sperm count.^[41] This was reinvestigated in a double blind controlled trial with 30mg saffron twice daily (60mg total each day) for 26 weeks in men with primary infertility but it failed to improve any measured seminal parameter (morphology, motility, density) and ejaculate volume relative to placebo.^[32]

The best evidence at this point in time does not support the hypothesis that saffron improves seminal parameters associated with male fertility.

The pathogenesis of asthma involves many inflammatory mediators.^[42] Due to saffron's anti-inflammatory effects in vitro,^[43] both saffron and some of its components have been studied in animal models of asthma to test its efficacy in this disease state.

One asthma model used guinea pigs sensitized to ovalbumin found that drinking water containing a 70% ethanolic extract of saffron (0.1-0.4 mg/mL) or safranal alone (4-16 μg/mL) improved some pathological signs of asthma in lungs. Serum histamine levels and some types of white blood cell (WBC) counts were also improved, although only safranal lowered total WBC count.^[44] A follow-up study also in guinea pigs using safranal alone (4-16 μg/mL) found a decreased tracheal response to methacholine as well as decreased nitric oxide and nitrite levels in the treated groups.^[45] This is significant since induced nitric oxide synthase (iNOS) activity has been shown to increase in asthma, and plays a roll in cellular damage.^[46] An in vitro experiment in human bronchial epithelial cells found that 10 ng/mL safranal reduced iNOS and brought nitric oxide levels down to an amount similar to control.^[47] In a mouse model of asthma, 10 mg/kg oral safranal for 7 days reduced iNOS as well as reducing inflammation and cell injury.^[47]

There have been some promising animal studies involving the use of either saffron extract or safranal in attenuating asthma signs. These results have not yet been confirmed in humans, however.

Saffron has been tested for its retinal protective properties as this is a function common to many carotenoids (astaxanthin and lutein) and the crocins have been implicated in similar protective effects.^[48] Preliminary evidence suggests that oral ingestion of 1mg/kg saffron extract (stigma) in rats exposed to continuous bright light prevented damage^[49][50] and performed mostly comparable to the reference drug (1mg/kg β-carotene).^[50] Supplementation for 10 days in rats appears to be more protective than supplementation over shorter periods of time (2-5 days) for light-induced retinal damage.^[51] In rodents, the protective effects appear to extend beyond light-induced damage, as as saffron prevents selenite-induced cataract formation.^[52]

The crocins, a type of carotenoid found in saffron, have protective effects in retinal tissue similar to other carotenoids, and their potency in rats seems comparable to other dietary carotenoids.

In patients with age-related macular degeneration (AMD), supplementation of 20mg saffron for three months increased the amplitude of focal electroretinograms (fERGs, which assesses cone sensitivity in early AMD^[53]) and reduced thresholds relative to baseline and placebo, which is suggestive of improvements in eye function; ophthalmoscopic appearance was unchanged, however.^[54] This has been noted elsewhere with saffron at 20mg daily when assessing whether the major risk genotypes of AMD, the complement factor H (CFH^[55]) and the age-related maculopathy susceptibility 2 (ARMS2^[56]) polymorphisms, affected the protective effects of saffron; neither did.^[57]

A human study failed to find carryover effects of saffron carotenoids through a crossover design, which suggests that, unlike other carotenoids, there is not a significant buildup of saffron carotenoids with supplementation, perhaps because saffron carotenoids are water-soluble, which is atypical for carotenoids.^[54] Animal data suggests there may be a minor buildup, however, as 10 days supplementation in rats is more effective than two or five days.^[51]

Human studies on age-related macular degeneration have noted benefits to visual acuity with saffron supplementation at slightly less than the standard oral dose. The benefits of supplementation have a rapid onset and lack prolonged benefits once supplementation is stopped, possibly due to the water solubility of these carotenoids, which leads to rapid elimination from the body.

PC-3 (prostatic cancer) cells incubated with 5-20µg/mL safranal were induced to undergo apoptosis by safranal, with an IC₅₀ value of 13.0+/-0.07µg/mL and 6.4+/-0.09µg/mL at 48 and 72 hours respectively, while nonmalignant cells (MRC-5) failed to undergo apoptosis when incubated with up to 20µg/mL safranal for over 72 hours.^[58]

When tested in vitro, crocins from the stigma of saffron appear to attenuate the formation of Aβ_1-40 protein fibrils in a concentration-dependent manner, with trans-crocin-4 inhibiting 15-40% of formation at 15−50μM.^[9] As trans-crocin-4 comprised around 10% of the crude extract and was 10-fold more potent than the crude extract and more effective than dimethylcrocetin, it was thought that trans-crocin-4 was then major active ingredient which worked through its antioxidant properties,^[9], as fibrillogenesis requires oxidation.^[59]

Crocins in saffron have been shown to reduce the formation of β-amyloid protein aggregates in vitro.

One 16-week study using saffron (15mg twice daily; conferring 260-300µg safranal and 3.3-3.5mg crocins) against placebo in persons with Alzheimer's disease noted significant benefits on ADAS-cog scores relative to placebo (3.69+/-1.69 point reduction versus placebo) and CDR-SB (0.67+/-0.24 reduction versus placebo).^[60]

A 22-week trial in people with mild to moderate Alzheimer's disease given 15mg saffron extract twice daily (once daily for the first four weeks) relative to the reference drug of 5mg donpezil twice daily and assessed by a variety of measurement scales on cognition (MMSE, ADAS-cog, and CDR-SB) found that although there was no difference found between the saffron and donpezil arms, both groups failed to show significant changes on ADAS-cog and CDR-SB from their baselines.^[61]

There is mixed human evidence as to the benefits of saffron on symptoms of mild to moderate Alzheimer's disease, with the only positive study being a reduced rate of decline (but not necessarily reduction of symptoms from baseline) while the other study noted that while saffron performed similarly to the reference drug donepezil, both failed to benefit symptoms.

The LD₅₀ of saffron petal and stigma extracts in mice via injections are 6g/kg and 1.6g/kg respectively^[62] while up to 3g/kg oral ingestion in mice is not acutely lethal.^[62]

Supplementation of saffron at doses higher than normal (200mg) in humans has been associated with some alterations in blood and hemodynamic parameters that, while statistically significant, where not of large enough magnitude to be considered adverse, although abnormal uterine bleeding was found in two women at doses of 200-400mg.^[28] Doses of 1,200-2,000mg saffron in humans can acutely cause symptoms such as nausea, vomiting, diarrhea, and bleeding.^[63]

More prolonged supplementation (26 weeks) with 60 mg saffron extract daily in men was associated with reductions in red and white blood cell counts as well as platelets, along with a drop in systolic and diastolic blood pressure of 10.8-11.7% and complaints of sedation, hypomania, and changes in appetite which started to occur after 8 weeks of exposure and increased in magnitude as the study proceded.^[32]

Saffron extract appears to be well-tolerated acutely at the normal doses (30mg daily), whereas higher doses for more prolonged periods can induce adverse effects.