February 17, 2014

A Whiff of Saffron Changes Hormone Levels in Women

Study shows saffron aromatherapy decreases cortisol and increases estrogen
Forty-seven female college students took part in a double-blind, placebo-controlled study involving short-term exposure to extracts of saffron. The study found that twenty minutes of exposure to the odor of saffron had a significant effect on these young women's hormone levels.


Fukui H, Toyoshima K, Komaki R. Psychological and neuroendocrinological effects of odor of saffron (Crocus sativus). Phytomedicine. 2011;18(8-9):726-730. 


A double-blind, placebo-controlled study involving short-term exposure (20 min) to stimuli.


Forty-seven female college students took part in this study. Of these, 36 were randomly assigned to a saffron group (n=36; 18 in follicular phase, 18 in luteal phase) or a control group (n=11; 5 in follicular phase, 6 in luteal phase). Each subject smelled either the saffron or control for 20 minutes. 
Study Medication and Dosage
Extracts of saffron were diluted in ethanol to such a degree that the smell of saffron could not be sensed. The control was a 76% ethanol and water only mixture.
Outcome Measures
Saliva samples were collected before and after a 20-minute period of sample inhalation. After the second sample was collected, a psychological test (the State-Trait Anxiety Inventory: STAI) was administered. The saliva was tested for levels of cortisol, testosterone, and 17-β estradiol (estrogen) by enzyme immunoassay.

Key Findings

Twenty minutes of exposure to the odor of saffron (even though diluted below recognition) had a significant effect on these young women: It decreased cortisol levels and increased estrogen levels. Twenty minutes of exposure to the ethanol alone that was used as a placebo also caused changes: It increased cortisol and decreased estrogen levels. 
Anxiety levels as measured by STAI score decreased in the saffron group. Saffron’s effects on cortisol and estrogen did not differ between the follicular- and luteal-phase groups.
Saffron may have lowered testosterone for women who were in the follicular phase and increased testosterone for those in the luteal phase, but these data did not reach statistical significance. 

Practice Implications

That the effects reported in this study could be achieved simply by inhaling saffron vapors comes as a welcome surprise. 
The herb we call saffron consists of the stigma of a small crocus. Harvesting saffron is highly labor intensive, and the resultant cost so high that economics argue against utilizing saffron as a medicine. Such cost concerns lose force if all that is required is a minute quantity of saffron to gain benefit. 
Agha-Hosseini et al reported in 2008 that taking 30 mg/day of saffron orally improved the symptoms of premenstrual syndrome (PMS). In their double-blind, placebo-controlled trial, significant improvements were seen in the Total Premenstrual Daily Symptoms and Hamilton Depression Rating Scale. It took 3–4 cycles to see results.1
These current papers follow 4 earlier randomized, double-blind, placebo-controlled human clinical trials in which saffron was shown to have significant benefit in treating depression. 
Two of these studies, one by Akhondzadeh et al and a second by Noorbala et al, both published in 2005, also used 30 mg of saffron a day in 6 week trials. Akhondzadeh’s group compared the effect of saffron against placebo, and Noobala compared saffron effect against the antidepressant medication fluoxetine (Prozac). Saffron produced significantly better results as measured on the Hamilton depression rating scale than the placebo (df=1, F=18.89, P<0.001). Noobala reported that the saffron effect was “similar to fluoxetine in the treatment of mild to moderate depression.”2,3
These researchers reported similar results in 2006 and 2007, but this time rather than using just the flower stigma, they used the flower petals. In November 2006 Moshiri et al reported that petals taken orally (30 mg/day) were again more effective than placebo in producing a significantly better outcome on Hamilton Depression Rating Scale (df=1, F=16.87, P<0.001).4 In March 2007, Akondzadeh et al reported that in an 8-week trial, petals (30 mg/day) were as effective as fluoxetine (10 mg/day) in treating mild to moderate depression.5 There would be an obvious economic advantage to using either the petals or the whole flower instead of only the stigma.
Thus we can view all of these trials as a progression from most expensive to least expensive therapeutic agent, moving from saffron, to flower petals, to odor alone. Whether or not the less expensive doses are as efficacious as saffron itself hasn’t been shown.
At first read the idea that a faint odor could have measurable physiologic effects strikes me as far-fetched. On second consideration we certainly have other examples of similar effect when we look at research on aromatherapy. Aromatherapy using lavender extracts is associated with reduced preoperative anxiety in both adult and pediatric surgical patients.6,7 One report suggests that lemon oil works even better than lavender.8
Recent investigations suggest that saffron may have clinical application for treating a variety of other disorders, including both neuronal and cardiovascular diseases and also malignancy. Of particular interest to are the recent papers suggesting a potential role in cancer treatment.9
The 12 months preceding last summer’s publication of the Fukui et al ‘saffron sniffing’ study, saw the publication of a stack of research papers on saffron and cancer. 
Recent investigations suggest that saffron may have clinical application for treating a variety of other disorders, including both neuronal and cardiovascular diseases and also malignancy.
An October 2011 study suggests a saffron extract called crocetin “significantly enhanced the cytotoxicity induced by vincristine” against cervical, non-small cell lung, ovarian, and breast cancer cell lines.10 Another October article describes using saffron in a liposomal form to increase cytoxic action against HeLa and MCF-7 cells.11 A May 2011 paper reported that “saffron exerts a significant chemopreventive effect against liver cancer through inhibition of cell proliferation and induction of apoptosis.”12 An April 2011 paper reported that crocetin “ affects the growth of cancer cells by inhibiting nucleic acid synthesis, enhancing antioxidative system, inducing apoptosis and hindering growth factor signaling pathways.”13 Papers from both May 2011 and 2010 suggest a potential benefit against lung cancer, the more recent telling us that “saffron could decrease the cell viability in the malignant cells as a concentration- and time-dependent manner…. [and could] be considered as a promising chemotherapeutic agent in lung cancer treatment in future.”14 An October 2010 had reached a similar conclusion: “The extract exerts pro-apoptotic effects in a lung cancer-derived cell line and could be considered as a potential chemotherapeutic agent in lung cancer.”15 A January 2011 paper reported that Crocetin inhibits invasiveness of breast cancer cells through downregulation of matrix metalloproteinases.”16 Other papers have suggested possible utility in treating pancreatic cancer and lymphoma.17,18,19
While the prospect of treating cancer through saffron aromatherapy is tempting, the crocetin fraction employed in these cancer studies is probably not delivered via aroma. The component likely responsible for the cortisol-lowering effect reported by Fukui et al is in likelihood a volatile agent, such as safranal. Crocetin, the saffron fraction typically investigated in these cytoxic reports, is a component generally considered to be a dye. It conveys color more than odor or taste. 
Thus, while it would be tempting to suggest to cancer patients that they start ‘sniffing’ saffron, actual cytotoxic effect will probably require oral consumption. At this point while no human trials of saffron for treating cancer have been published, we can certainly justify saffron use by cancer patients to help relieve complaints of anxiety. That these medications might also convey a cytoxic effect is a possibility and one that we will certainly be watching the literature for over the coming years to see if it is confirmed. Though in theory the petals of the saffron crocus may be far more economical, it is unclear whether they are yet commercially available. Certainly some enterprising botanical supplier should be taking advantage of this lower price and seemingly equivalent efficacy in the near future and supplying capsules of crocus petals.

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  1.  Agha-Hosseini M, Kashani L, Aleyaseen A, et al. Crocus sativus L. (saffron) in the treatment of premenstrual syndrome: a double-blind, randomised and placebo-controlled trial. BJOG. 2008;115(4):515-519.
  2.  Akhondzadeh S, Tahmacebi-Pour N, Noorbala AA, et al. Crocus sativus L. in the treatment of mild to moderate depression: a double-blind, randomized and placebo-controlled trial. Phytother Res. 2005;19(2):148-151.
  3.  Noorbala AA, Akhondzadeh S, Tahmacebi-Pour N, Jamshidi AH. Hydro-alcoholic extract of Crocus sativus L. versus fluoxetine in the treatment of mild to moderate depression: a double-blind, randomized pilot trial. J Ethnopharmacol. 2005;97(2):281-284.
  4.  Moshiri E, Basti AA, Noorbala AA, Jamshidi AH, Hesameddin Abbasi S, Akhondzadeh S. Crocus sativus L. (petal) in the treatment of mild-to-moderate depression: a double-blind, randomized and placebo-controlled trial. Phytomedicine. 2006;13(9-10):607-611.
  5.  Akhondzadeh Basti A, Moshiri E, Noorbala AA, Jamshidi AH, Abbasi SH, Akhondzadeh S. Comparison of petal of Crocus sativus L. and fluoxetine in the treatment of depressed outpatients: a pilot double-blind randomized trial.
  6. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(2):439-442.
  7.  Braden R, Reichow S, Halm MA. The use of the essential oil lavandin to reduce preoperative anxiety in surgical patients. J Perianesth Nurs. 2009;24(6):348-355.
  8.  Nord D, Belew J. Effectiveness of the essential oils lavender and ginger in promoting children's comfort in a perianesthesia setting. J Perianesth Nurs. 2009;24(5):307-312.
  9.  Kiecolt-Glaser JK, Graham JE, Malarkey WB, Porter K, Lemeshow S, Glaser R. Olfactory influences on mood and autonomic, endocrine, and immune function. Psychoneuroendocrinology. 2008;33(3):328-339.
  10.  Bathaie SZ, Mousavi SZ. New applications and mechanisms of action of saffron and its important ingredients. Crit Rev Food Sci Nutr. 2010;50(8):761-786.
  11.  Zhong YJ, Shi F, Zheng XL, et al. Crocetin induces cytotoxicity and enhances vincristine-induced cancer cell death via p53-dependent and -independent mechanisms. Acta Pharmacol Sin. 2011;32(12):1529-1536.
  12.  Mousavi SH, Moallem SA, Mehri S, Shahsavand S, Nassirli H, Malaekeh-Nikouei B. Improvement of cytotoxic and apoptogenic properties of crocin in cancer cell lines by its nanoliposomal form. Pharm Biol. 2011;49(10):1039-1045.
  13.  Amin A, Hamza AA, Bajbouj K, Ashraf SS, Daoud S. Saffron: A potential candidate for a novel anticancer drug against hepatocellular carcinoma. Hepatology. 2011;54(3):857-867.
  14.  Gutheil WG, Reed G, Ray A, Dhar A. Crocetin: an agent derived from saffron for prevention and therapy for cancer. Curr Pharm Biotechnol. 2012 Jan;13(1):173-179.
  15.  Samarghandian S, Tavakkol Afshari J, Davoodi S. Suppression of pulmonary tumor promotion and induction of apoptosis by Crocus sativus L. extraction. Appl Biochem Biotechnol. 2011;164(2):238-247.
  16.  Samarghandian S, Boskabady MH, Davoodi S. Use of in vitro assays to assess the potential antiproliferative and cytotoxic effects of saffron (Crocus sativus L.) in human lung cancer cell line. Pharmacogn Mag. 2010;6(24):309-314.
  17.  Chryssanthi DG, Dedes PG, Karamanos NK, Cordopatis P, Lamari FN. Crocetin inhibits invasiveness of MDA-MB-231 breast cancer cells via downregulation of matrix metalloproteinases. Planta Med. 2011;77(2):146-151.
  18.  Bakshi H, Sam S, Rozati R, et al. DNA fragmentation and cell cycle arrest: a hallmark of apoptosis induced by crocin from kashmiri saffron in a human pancreatic cancer cell line. Asian Pac J Cancer Prev. 2010;11(3):675-679.
  19.  Dhar A, Mehta S, Dhar G, et al. Crocetin inhibits pancreatic cancer cell proliferation and tumor progression in a xenograft mouse model. Mol Cancer Ther. 2009;8(2):315-323.
  20.  Bakshi HA, Sam S, Feroz A, Ravesh Z, Shah GA, Sharma M. Crocin from Kashmiri saffron (Crocus sativus) induces in vitro and in vivo xenograft growth inhibition of Dalton's lymphoma (DLA) in mice. Asian Pac J Cancer Prev. 2009;10(5):887-890