Saffron Floats

by Jacob Schor, ND, FABNO

One could say that great minds think alike. It might be more accurate to say that eccentric minds sometimes get lost in similar parallel universes.

My colleague Mark Davis, the naturopath of dubious fame for being the fecal transplant expert, was our houseguest for a few days last November.

Over morning coffee, we realized that both of us had been engaged in a similar experiment, mixing dried saffron filaments with honey and adding the mixture to our morning coffee. We had both independently thought that this would be a great idea. If you stir 1 gram of saffron into half a cup of honey, each teaspoon will, in theory, provide about 30 mg of saffron. One could make a cup of saffron tea by simply adding a spoon of this saffronized honey to hot water and end up with a decent dose of saffron in it. We were both past drinking saffron tea; we were stirring our saffron laced honey into our morning coffee.

It turned out that both of us had notice the saffron studies published over the past few years. The papers that initially grabbed our attention focused on psychological effects.

Agha-Hosseini reported back in 2008 that taking 30 mg/day of saffron improved premenstrual syndrome symptoms (PMS). Improvements were seen in the Total Premenstrual Daily Symptoms and Hamilton Depression Rating Scale. It did take 3 to 4 menstrual cycles to see results, though.¹

Four earlier human clinical trials had shown that saffron significantly relieved depression. Two of these studies, one by Akhondzadeh and a second by Noorbala, both published in 2005, used 30 mg of saffron a day in 6-week trials. Akhondzadeh compared saffron against placebo, while Noobala compared saffron effect against the fluoxetine [Prozac]. Saffron worked better against depression than the placebo and better than the Prozac.^2,3

These researchers reported similar results in 2006 and 2007 but used stigma and flower petals rather than just the stigma. In November 2006, Moshiri reported that petals (30 mg/day) were more effective than placebo.⁴ In March 2007, Akondzadeh 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

A review by Kazdair et al. published in September 2015 lists a range of actions:

Saffron has been suggested to be effective in the treatment of a wide range of disorders including coronary artery diseases, hypertension, stomach disorders, dysmenorrhea and learning and memory impairments. In addition, different studies have indicated that saffron has anti-inflammatory, anti-atherosclerotic, antigenotoxic and cytotoxic activities. Antitussive effects of stigmas and petals of C. sativus and its components, safranal and crocin have also been demonstrated. The anticonvulsant and anti-Alzheimer properties of saffron extract were shown in human and animal studies. The efficacy of C. sativus in the treatment of mild to moderate depression was also reported in clinical trial. Administration of C. sativus and its constituents increased glutamate and dopamine levels in the brain in a dose-dependent manner. It also interacts with the opioid system to reduce withdrawal syndrome.⁶

Another review, published a few months earlier in July 2015, combined data from 12 earlier clinical trials “examining the effectiveness of saffron (Crocus sativus L.) on psychological and behavioral outcomes.” The conclusion, “saffron may improve the symptoms and the effects of depression, premenstrual syndrome, sexual dysfunction and infertility, and excessive snacking behaviors.”⁷

The idea that saffron has value in treating depression is certainly quite old. In Greek mythology, Crocus was a mortal youth who became overly enamored with the nymph Smilax. He was left forlorn when she grew bored with him. The gods turned him into the crocus flower that we obtain saffron from. Smilax was also turned into a flower, one that we call bindweed. ⁸

In yet another meta-analysis, this one from September 2014, Lopresti and Drummund combined data from six randomized placebo-controlled trials and concluded, “Saffron had large treatment effects and, when compared with antidepressant medications, had similar antidepressant efficacy. Saffron’s antidepressant effects potentially are due to its serotonergic, antioxidant, anti-inflammatory, neuro-endocrine and neuroprotective effects.”⁹

Obviously, using whole flowers would be more cost effective than stigmata. Fukui tested an even more cost-effective idea in 2011. Study participants were asked to simply smell a tincture of saffron several times a day. The saffron was dilute enough that the participants could not detect whether they had the tincture that contained saffron or the placebo. This no-cost intervention nevertheless significantly changed cortisol and other serum markers.¹⁰ Fukui’s study encouraged Dr. Davis and me to favor saffron tea over capsules, as it might act in part via an aromatherapy effect.

Saffron’s effect on cancer is of great interest. Most if not all cancer patients will experience some degree of depression, and the idea that an effective antidepressant might also provide benefits against cancer is attractive. An October 2011 study reported that a molecular constituent of saffron called crocetin “significantly enhanced the cytotoxicity induced by vincristine” against cervical, NSCLC, ovarian, and breast cancer cell lines.¹¹ Another October article described using saffron in a liposomal form to increase cytotoxic action against HeLa and MCF-7 cells.¹² A May 2011 paper reported that “saffron exerts a significant chemopreventive effect against liver cancer through inhibition of cell proliferation and induction of apoptosis.”¹³ An April 2011 paper reported that crocetin “affects the growth of cancer cells by inhibiting nucleic acid synthesis, enhancing anti-oxidative system, inducing apoptosis and hindering growth factor signaling pathways.”¹⁴ Papers from both May 2011 and 2010 suggest a potential benefit against lung cancer, the more recent telling us, “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.”¹⁵ An October 2010 paper 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.”¹⁶ A January 2011 paper reported that “Crocetin inhibits invasiveness of breast cancer cells through downregulation of matrix metalloproteinases.”¹⁷ Other papers have suggested possible utility in treating pancreatic cancer and lymphoma.^18–20

Hosseni et al. reported in September 2015 the results of their small clinical trial in which 13 patients with cancer metastasized to the liver were divided into two groups. Both groups received standard chemotherapy treatment. Patients in one group received 50 mg of saffron in a capsule twice a day during chemotherapy, while the second group received placebo. Of the 13 patients who started, only 7 finished the study. Two of the 4 patients who took saffron showed a partial and complete response. No response was seen in the placebo group. Admittedly, the sample size is too small for this study to be convincing. On the other hand, most of us would probably volunteer to get the saffron if we offered and not the placebo.²¹

A September 2015 article published in Oncotarget by Rangarajan and fellow researchers at Kansas University describes an experiment in mice which suggests that saffron extracts strikingly inhibit pancreatic cancer cell growth in both cell cultures and in mice. “The mice who were given the crocetinic acid demonstrated a 75 percent reduction in their tumor growth, while the mice in the control group, which didn’t receive the crocetinic acid, actually saw a 250 percent increase in tumor growth.”²²

Saffron continues to appear quite safe to use, even in high-risk patient populations. A September 2015 paper by Mousavi et al. reported on a double-blind, placebo-controlled study performed on patients with schizophrenia. A total of 66 male patients were divided into three groups. While receiving their normal treatment, they also received a 12-week treatment with an aqueous extract of saffron (15 mg twice daily), crocin (15 mg twice daily), or placebo. Sixty-one patients completed the trial; none of them reported a serious side effect. White blood cell counts increased significantly in patients receiving saffron aqua extract, but it was within the normal range and had no clinical significance. Other hematologic components, markers of thyroid, liver and kidney, or inflammation markers had no statistically significant difference among the groups.²³

Recent publications suggest that saffron has benefit for a range of other conditions. Human clinical trials have been published in the last year or two, suggesting a benefit in depression, Alzheimer’s disease, glaucoma, macular degeneration, and erectile dysfunction.^24–29

Studies on depression have advanced, moving from treating patients with mild to moderate depression in 2014 to a study on treating major depressive disorders in 2015.^30,31

I used to tell patients interested in taking saffron that they should make a water alcohol extraction, adding half an ounce of boiling water to a gram of saffron, letting it steep for a few days and then adding an equal volume of vodka and dosing it by the drop. While that method remains sound, both Mark Davis and I apparently simultaneously tried the same experiment; we both mixed a gram of saffron into half a cup of honey. Dr. Davis isn’t the only colleague who shares my interest in saffron; I’ve been trading abstracts and full text articles on saffron with Dr. Davis Lamson, the other “Davis” in my world.

There is something emotionally touching to find both “Davis Senior” and “Davis Junior,” the former being more than twice the age of the younger, fascinated by the same herb. It brings a sensation of confluence; we have all independently adopted the same therapy at the same time into our practices. To my amusement, Davis Lamson’s method of calculating the dose of milligrams saffron per teaspoon of honey suspension was far more complicated and involved convoluted conversions of cups to milliliters then back to teaspoons, while Mark Davis and I took the simple route of simply dividing 1000 mg/gm by 24 tsp/ half-cup honey; we all ended up with about 42 mg saffron/ tsp honey.

In the end, this honey suspension experiment did not work as well as Dr. Davis and I had hoped. Saffron is so very light; despite how viscous honey is, the saffron floats to the top of the honey. Dr. Davis has already modified his approach and meticulously hand-grinds the saffron filaments with a mortar and pestle before mixing it in. I take a simpler approach; when the saffron floats to the top, I just stir it back in. It isn’t a big deal.

I find myself feeling quite pleased with this saffron business. Perhaps it is all the saffron I’ve consumed of late. I think it is something else. The idea that Dr. Davis, Dr. Lamson, and I have wandered along our own paths to arrive at much the same place at the same time is pleasing. It is nice to find oneself in such fine company.

Notes

1. Agha-Hosseini M, Kashani L, Aleyaseen A, Ghoreishi A, et al. Crocus sativus L. (saffron) in the treatment of premenstrual syndrome: a double-blind, randomised and placebo-controlled trial. BJOG. 2008 Mar;115(4):515–9.

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 Feb;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 Feb 28;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 Nov;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. Prog Neuropsychopharmacol Biol Psychiatry. 2007 Mar 30;31(2):439–442.

6. Khazdair MR, Boskabady MH, Hosseini M, Rezaee R, M Tsatsakis A. The effects of Crocus sativus (saffron) and its constituents on nervous system: A review. Avicenna J Phytomed. 2015 Sep–Oct;5(5):376–391.

7. Hausenblas HA, Heekin K, Mutchie HL, Anton S. A systematic review of randomized controlled trials examining the effectiveness of saffron (Crocus sativus L.) on psychological and behavioral outcomes. J Integr Med. 2015 Jul;13(4):231–240.

8. Ovid. Metamorphosis. 4:274–316.

9. Lopresti A1, Drummond PD. Saffron (Crocus sativus) for depression: a systematic review of clinical studies and examination of underlying antidepressant mechanisms of action. Hum Psychopharmacol. 2014 Nov;29(6):517–527.

10. Fukui H, Toyoshima K, Komaki R. Psychological and neuroendocrinological effects of odor of saffron (Crocus sativus). Phytomedicine. 2011 Jun 15;18(8–9):726–730.

11. Zhong YJ, Shi F, Zheng XL, Wang Q, Yang L, Sun H, et al. Crocetin induces cytotoxicity and enhances vincristine-induced cancer cell death via p53-dependent and -independent mechanisms. Acta Pharmacol Sin. 2011 Oct 10. doi:10.1038/aps.2011.109.

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 Oct;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 May 23. doi:10.1002/hep.24433.

14. Gutheil WG, Reed G, Ray A, Dhar A. Crocetin: an agent derived from saffron for prevention and therapy for cancer. Curr Pharm Biotechnol. 2011 Apr 5.

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 May;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 Oct;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 Jan;77(2):146–51. Epub 2010 Aug 27.

18. Bakshi H, Sam S, Rozati R, Sultan P, Islam T, Rathore B, 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 Feb;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.

21. Hosseini A, Mousavi SH, Ghanbari A, et al. Effect of saffron on liver metastases in patients suffering from cancers with liver metastases: A randomized, double blind, placebo-controlled clinical trial. Avicenna J Phytomed. 2015 Sep–Oct;5(5):434–440.

22. Rangarajan P, Subramaniam D, Paul S, et al. Crocetinic acid inhibits hedgehog signaling to inhibit pancreatic cancer stem cells. Oncotarget. 2015 Sep 29;6(29):27661–27673. doi:10.18632/oncotarget.4871.

23. Mousavi B, Bathaie SZ, Fadai F, et al. Safety evaluation of saffron stigma (Crocus sativus L.) aqueous extract and crocin in patients with schizophrenia. Avicenna J Phytomed. 2015 Sep–Oct;5(5):413–419.

24. Shahmansouri N, Farokhnia M, Abbasi SH, et al. A randomized, double-blind, clinical trial comparing the efficacy and safety of Crocus sativus L. with fluoxetine for improving mild to moderate depression in post percutaneous coronary intervention patients. J Affect Disord. 2014 Feb;155:216–222.

25. Talaei A, Hassanpour Moghadam M, Sajadi Tabassi SA, Mohajeri SA. Crocin, the main active saffron constituent, as an adjunctive treatment in major depressive disorder: a randomized, double-blind, placebo-controlled, pilot clinical trial. J Affect Disord. 2015 Mar 15;174:51–56.

26. Farokhnia M, Shafiee Sabet M, Iranpour N, et al. Comparing the efficacy and safety of Crocus sativus L. with memantine in patients with moderate to severe Alzheimer’s disease: a double-blind randomized clinical trial. Hum Psychopharmacol. 2014 Jul;29(4):351–359.

27. Jabbarpoor Bonyadi MH, Yazdani S, Saadat S. The ocular hypotensive effect of saffron extract in primary open angle glaucoma: a pilot study. BMC Complement Altern Med. 2014 Oct 15;14:399. doi:10.1186/1472-6882-14-399.

28. Marangoni D, Falsini B, Piccardi M, et al. Functional effect of Saffron supplementation and risk genotypes in early age-related macular degeneration: a preliminary report. J Transl Med. 2013 Sep 25;11:228. doi:10.1186/1479-5876-11-228.

29. Mohammadzadeh-Moghadam H, Nazari SM, et al. Effects of a topical saffron (Crocus sativus L) gel on erectile dysfunction in diabetics: a randomized, parallel-group, double-blind, placebo-controlled trial. J Evid Based Complementary Altern Med. 2015 Oct;20(4):283–286.

30. Shahmansouri N, Farokhnia M, Abbasi SH, et al. A randomized, double-blind, clinical trial comparing the efficacy and safety of Crocus sativus L. with fluoxetine for improving mild to moderate depression in post percutaneous coronary intervention patients. J Affect Disord. 2014 Feb;155:216–222.

31. Talaei A, Hassanpour Moghadam M, Sajadi Tabassi SA, Mohajeri SA. Crocin, the main active saffron constituent, as an adjunctive treatment in major depressive disorder: a randomized, double-blind, placebo-controlled, pilot clinical trial. J Affect Disord. 2015 Mar 15;174:51–56.