Saffron

Generic name: Crocus Sativus L.
Brand names: Saffron, Stigma Croci, Za'faran

Usage of Saffron

Anti-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

A systematic review of data from randomized controlled trials identified 6 studies that met inclusion criteria that investigated oral spice supplementation for rheumatoid arthritis. One double-blind study assessed saffron 100 mg daily or placebo for 12 weeks in 66 adults with active disease with at least a 2-year disease duration. Compared to placebo, saffron significantly improved 4 of 7 outcome measures (P=0.028 to P<0.001), including disease activity erythrocyte sedementation rate score, swollen joint count, and pain.(89)

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)

In a double-blind, randomized, controlled trial that enrolled 60 obese men with type 2 diabetes, significant improvements in levels of inflammatory biomarkers (hs-CRP, interleukin [IL]-1beta, IL-6, tumor necrosis factor-alpha) and the anti-inflammatory cytokine IL-10 were observed in all 3 intervention groups (training alone, saffron alone, training plus saffron) compared to controls (P<0.001 for 14 comparisons, P=0.014 for 1 comparison). However, men in the training plus saffron group demonstrated significantly greater changes compared to the other 2 intervention groups (P≤0.001 for 10 comparisons, P=0.036 and P=0.037 for the other 2 comparisons). The intervention period was 12 weeks and pure saffron capsules were dosed at 100 mg/day. Body fat percentage was positively and significantly correlated with each of the biomarkers assessed.(92)

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 extracts(5); 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 elderly hypertensive men enrolled in a small randomized controlled trial (N=48), supplementation of saffron 200 mg/day for 12 weeks improved blood pressure compared to controls (P<0.001) with greater effects seen when combined with resistance training. Adiponectin levels also increased significantly (P=0.012) and the vasoconstrictor, endothelin-1, decreased significantly with saffron (P<0.001), resistance training, and the combination of both.(90)

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)

Dementia

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)

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 12 weeks in treating mild to moderate depression.(5, 33, 34, 35, 36, 37, 38, 39, 40, 41, 87) 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. No differences in adverse events were noted 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) In patients with mild to moderate depression refractory to a single pharmaceutical antidepressant, adjunctive administration of a standardized saffron extract derived from stigmas (affron; 14 mg twice daily for 8 weeks) resulted in significant improvement in depression scores rated by clinicians (P=0.002) but not in those rated by the participants themselves. A total of 160 participants were enrolled in this double-blind, randomized, placebo-controlled trial.(86) In women with mild to moderate major depressive disorder (MDD) and comorbid obesity who were prescribed a weight loss diet, saffron 30 mg/day for 12 weeks was found to produce a significant reduction in depression score compared to placebo (P=0.007), but not in food craving or appetite measures.(87)

In a double-blind, randomized, placebo-controlled trial, 60 patients with mild to moderate mixed anxiety and depression were assigned to saffron (50 mg twice daily) or placebo for 12 weeks. A significant effect was observed with saffron compared to placebo for anxiety as well as depression scores (P<0.001 for each).(91)

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 MDD in adults (2016) recommend saffron as third-line monotherapy or adjunctive therapy for mild to moderate MDD (Level 2).(45)

Metabolic effects

Clinical data

Secondary outcomes assessed in a double-blind, randomized, controlled trial that enrolled 60 obese men with type 2 diabetes demonstrated significant reductions in Fasting plasma glucose, insulin resistance, insulin levels, and HbA1c in all 3 interventions groups (training alone, saffron alone, training plus saffron) compared to controls (P<0.001 for 11 comparisons, P=0.013 for 1 comparison). However, men in the training plus saffron group demonstrated significantly greater changes compared to the other 2 intervention groups (P≤0.001 for 10 comparisons; P=0.003 and P=0.006 for 2 comparisons). The intervention period was 12 weeks and pure saffron capsules were dosed at 100 mg/day. Similar results were observed in anthropomorphic parameters (ie, body mass, body mass index, waist-hip ratio, body fat percentage).(92) Another double-blind, randomized, placebo-controlled study conducted in 70 overweight/obese adults with type 2 diabetes for at least 6 months reported significant improvements in several glycemic, lipid, and liver parameters with saffron 100 mg/day compared to placebo. Fasting blood glucose (P=0.04), insulin levels (P=0.03), insulin resistance (P=0.01), triglycerides (P=0.004), total cholesterol (P=0.001), low-density lipoprotein (LDL) (P=0.008), AST (P=0.002), and ALT (P=0.01) were all improved with saffron compared to placebo. No significant differences between groups were observed for HbA1c or high-density lipoprotein. The majority of these parameters also improved significantly compared to baseline with saffron, while LDL (P=0.03) and AST (P=0.003) worsened significantly compared to baseline in the placebo group. No adverse events were reported. Additionally, depression index scores, diabetes-specific quality of life, and several sleep parameters (ie, quality, duration, efficiency, Daytime functioning, and global sleep quality) were significantly improved with saffron compared to placebo (range, P<0.001 to P=0.04). No changes in sexual function scores were noted.(94)

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 effects(67, 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 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)

Premenstrual syndrome

Clinical data

Limited clinical studies suggest efficacy in premenstrual syndrome(53, 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) A double-blind, randomized, placebo- and active-controlled study that enrolled 120 Iranian women with premenstrual dysphoric disorder identified a significant improvement only between saffron and placebo scores for Daily Record of Severity of Problems (DRSP; P=0.027). No significant difference was found between fluoxetine and saffron or placebo in DRSP scores, and no differences were found among the groups in Hamilton severity assessments. Compared to baseline, all 3 groups demonstrated significant improvements in both DRSP and Hamilton scores. Women received saffron 15 mg, fluoxetine 20 mg, or placebo twice daily for 14 days in the luteal phase of the menstrual cycle for 2 cycles. Fewer side effects were experienced in the saffron group (20%) compared to fluoxetine (52.5%) and placebo (37.5%). Increased menorrhagia (12.5%) was the most commonly reported adverse event in saffron users.(88)

Satiety

Clinical data

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) In 73 obese women with mild to moderate MDD, no difference was observed in food craving or appetite measures for saffron 30 mg/day for 12 weeks compared to placebo in a double-blind, randomized, controlled trial.(87)

Other uses

Immunomodulatory effects have been described.(73)

No effects on sperm density, morphology, and motility were reported in limited clinical studies.(60, 61)

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)

Saffron side effects

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

Before taking Saffron

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.

How to use Saffron

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

Warnings

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

What other drugs will affect Saffron

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)

Rivaroxaban: Saffron may enhance the anticoagulant effect of rivaroxaban. Monitor therapy.(27, 93)

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