Saffron (from Arabic/Persian ‘the yellow’, “saffron”), Crocus sativus, is a crocus species that flowers violet in autumn and is mainly used as a spice plant: from the stigmas of its flowers (the “styles”) the spice likewise called saffron is obtained. This plant species is a triploid mutant of Crocus cartwrightianus, native to the Aegean islands. It is sterile because of its triple chromosome set and can only be propagated vegetatively by corm division. The ancestral form Crocus cartwrightianus has noticeably shorter, but likewise aromatic stigmas. Saffron is cultivated in Afghanistan, Iran, Kashmir, Morocco, Turkey, southern France, Greece, Italy, Spain and Austria. Although saffron is among the renewable raw materials, at up to EUR 20,000/kg it is a luxury commodity, of which up to 95 % comes from Iran. About 200,000 flowers are needed for 1 kg of stigma filaments [1].
Use of saffron
Saffron has held an important place in oriental medicine for thousands of years [1]. Published clinical studies have shown that saffron has a mood-lifting effect in mild to moderate forms of depression [18]. Because of the possible anti-inflammatory and antioxidant effects of saffron, preparations containing saffron are worth discussing for the treatment of rheumatic disease [2, 17].
In Germany 46 saffron-containing preparations are listed; however, most of them are not classified as medicinal products. Only a few preparations are offered as herbal over-the-counter, pharmacy-only medicinal products (Crocus sativus) (source: Gelbe Liste Pharmindex [4]), for example:
Saffron capsules 60 and 120 units, PZN 06055479, Diamant Natuur B.V. s.r.o.
Saffron + sage capsules 120 and 240 units, Diamant Natuur B.V. s.r.o. [5].
The product information for the above preparations reads “... registered homeopathic medicinal product”, but without specifying a therapeutic indication. Source: information on the packaging (as of 09/2022) [6].
Chemical and pharmacological composition
Saffron contains carotenoids (crocin, crocetin), so that dishes seasoned with saffron take on an intense golden-yellow colour. It also contains the bitter substance picrocrocin, from which the aldehyde safranal — responsible for the saffron aroma — is partly formed during drying. Other aromatic substances include isophorones [1].
Effects in vitro and in animal models
In one study, the effect of crocin in vivo was tested using a mouse model of collagen-induced arthritis (CIA). In-vivo results showed that treatment with crocin significantly reduced plasma levels of TNF-α, IL-1β and IL-6 in CIA mice. Crocin apparently blocks activation of the NF-κB signal through its interaction with LPS-induced p-IκBα and p-IκB kinase IKK [8].
The effects of intake of Krocina™, a crocin-containing natural product, on the expression of transcription factors of various T-cell lines were examined in 40 patients with osteoarthritis. In the comparison group, 40 patients with osteoarthritis received a placebo preparation. The significant increase in gene expression of GATA-3 (transcription factor) under the verum could indicate a positive effect of crocin on the differentiation of T cells into Th2 cells and an anti-inflammatory effect [9]. In a further controlled study, the effects of crocin on the expression of matrix metalloproteinases (MMP-1, MMP-3 and MMP-13) in chondrocytes were investigated in a rabbit osteoarthritis model. In-vivo investigations showed that crocin improved cartilage regeneration and that the expression of the MMP-1, -3 and -13 genes in cartilage was significantly inhibited by crocin [10].
A PubMed search for scientific articles using the keyword “Saffron (Crocus sativus)” (as of 06 March 2024) yielded 199 references, for the keyword “Crocin” 86, for “Crocetin” 40 and for “Safranal” 29 references. The clinical studies predominantly concern non-rheumatological indications such as sleep disorders, depression, diabetes, renal insufficiency and arterial hypertension. There were 32 meta-analyses on saffron. The majority of these dealt with the efficacy of saffron in sleep disorders and depression [3].
Use of medicinal products based on saffron for rheumatological indications
Of 125 studies, only five RCTs met these criteria [12]. These RCTs included patients with RA, OA and fibromyalgia and assessed as outcomes pain, disease activity, depression, immune response, inflammation, oxidative stress, general health, fatigue and functional capacity. Most studies showed flawed designs. Thus, the majority of study authors did not adhere to the criteria established for RCTs in the ConsolidatA meta-analysis summarised the available studies on Crocus sativus in rheumatic diseases (from PubMed, CENTRAL, Clinicaltrials.gov as well as non-PubMed-listed and non-English literature up to October 2021) and further analysed relevant randomised controlled trials (RCTs). The risk of “bias” (i.e. the examination of study data for trustworthiness) was considered according to the Cochrane criteria [19].ed Standards of Reporting Trials (CONSORT) statement [20]. Because of the great heterogeneity and the lack of information on standardisation and content of the saffron preparations used, it was concluded that the evidence is insufficient to demonstrate either efficacy or lack of efficacy [12].
Of the five studies that met the inclusion criteria for RCT in the above-mentioned analysis [12], only three were listed in PubMed, with the following results:
In a randomised, double-blind, placebo-controlled 12-week study, 66 women aged over 18 years with active RA received daily either 100 mg of a saffron preparation (n = 33) or a corresponding placebo (n = 33). No adverse effects were reported by the patients. Saffron supplementation significantly reduced the number of tender (p < 0.001) and swollen (p < 0.001) joints, the pain intensity (p < 0.001) and the DAS28 (p < 0.001). The physician’s global assessment (p = 0.002), the erythrocyte sedimentation rate and CRP were significantly improved after the intervention [11].
A double-blind, placebo-controlled, randomised clinical trial (RCT) was carried out in 55 newly diagnosed RA patients receiving standard therapy (with prednisolone, oral methotrexate, folic acid, vitamin D, calcium and alendronate) with and without 100 mg saffron/day (pure saffron powder in tablet form) (study duration 90 days). In patients who received pure saffron tablets in addition to standard therapy, no significant difference in the improvement of disease activity was observed compared to patients on standard therapy [7].
In a double-blind clinical parallel-group study, 65 outpatients with fibromyalgia were randomised and received either 15 mg of saffron or 30 mg of duloxetine, starting with 1 capsule per day in the first week, followed by 2 capsules per day from week 2 to the end of week 8. For none of the scales (Hamilton Rating Scale for Depression, Fibromyalgia Impact Questionnaire, Brief Pain Inventory) was a significant difference in score changes from baseline to endpoint observed between the two treatment arms. Saffron and duloxetine showed comparable significant positive efficacy in the treatment of FM [13]. However, given the small case number, it is questionable whether the study had sufficient statistical power for a non-inferiority analysis.
The experimental studies suggest that crocin, as a constituent of saffron, could be a potentially effective agent in inflammatory joint diseases [8].
However, the current data from clinical studies on saffron preparations are not sufficient for a positive recommendation. In this context the current recommendations of the French Society of Rheumatology should also be cited: “dietary supplementation with saffron could have a positive effect on RA activity, but the data are too limited to recommend saffron preparations in daily practice” [14].
The risk of relevant adverse effects from oral saffron preparations is considered low [15, 18]. In clinical studies in the field of neurological diseases, 30 mg/day of saffron (use over up to 12 months) caused no significant adverse effects compared with control. Reported events include, for example, gastrointestinal complaints, fatigue, dizziness, headache, dry mouth, etc. in patients, but not in healthy individuals [16]. In a double-blind, placebo-controlled study with 30 healthy volunteers, the safety of 200 and 400 mg of saffron per day was tested for one week. 400 mg/day of saffron decreased systolic blood pressure as well as the haemoglobin value and the red blood cell count compared with placebo. However, these changes remained within the reference range [21].
The scientific evidence is insufficient to recommend the prescription and use of saffron preparations for patients with inflammatory rheumatic diseases.
Last updated: September 28, 2024