1Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
2Pharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
3Neurocognitive Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
Saffron (Crocus sativus L.) has been considered as a medicinal plant since ancient times and also widely used as food additive for its color, taste and odor. The pharmacological properties of saffron and its main constituents, crocin and safranal have been evaluated using different in vivo and in vitro models. Additionally, other lines of studies have found toxicological effects of saffron. However, a comprehensive review that covers all aspects of its toxicity has not been published yet. The current study provides classified information about the toxic effects of saffron and its constituents in various exposure conditions including acute, sub-acute, sub-chronic and chronic studies. Therapeutic doses of saffron exhibits no significant toxicity in both clinical and experimental investigations.
1. Razavi BM, Hosseinzadeh H. Saffron as an antidote or a protective agent against natural or chemical toxicities. Daru 2015; 23:31.
2. Mollazadeh H, Emami SA, Hosseinzadeh H. Razi’s Al-Hawi and saffron (Crocus sativus): a review. Iran J Basic Med Sci 2015; 18:1153-1166.
3. Rezaee R, Hosseinzadeh H. Safranal: from an aromatic natural product to a rewarding pharmacological agent. Iran J Basic Med Sci 2013; 16:12.
4. Alavizadeh SH, Hosseinzadeh H. Bioactivity assessment and toxicity of crocin: a comprehensive review. Food Chem Toxicol 2014; 64:65-80.
5. Hosseinzadeh H. Saffron: a herbal medicine of third millennium. Jundishapur J Nat Pharm Prod 2014; 9:1-2.
6. Hosseinzadeh H, Nassiri-Asl M. Avicenna's (Ibn Sina) the Canon of Medicine and saffron (Crocus sativus): a review. Phytother Res 2013; 27:475-483.
7. Imenshahidi M, Razavi BM, Faal A, Gholampoor A, Mousavi SM, Hosseinzadeh H. Effects of chronic crocin treatment on desoxycorticosterone acetate (doca)-salt hypertensive rats. Iran J Basic Med Sci 2014; 17:9-13.
8. Amin B, Malekzadeh M, Heidari MR, Hosseinzadeh H. Effect of Crocus sativus extracts and its active constituent safranal on the harmaline-induced tremor in mice. Iran J Basic Med Sci 2015; 18:449-458.
9. Mehri S, Abnous K, Khooei A, Mousavi SH, Shariaty VM, Hosseinzadeh H. Crocin reduced acrylamide-induced neurotoxicity in Wistar rat through inhibition of oxidative stress. Iran J Basic Med Sci 2015; 18:902-908.
10. Dorri SA, Hosseinzadeh H, Abnous K, Hasani FV, Robati RY, Razavi BM. Involvement of brain-derived neurotrophic factor (BDNF) on malathion induced depressive-like behavior in subacute exposure and protective effects of crocin. Iran J Basic Med Sci 2015; 18:958-966
11. Hosseinzadeh H, Motamedshariaty V, Hadizadeh F. Antidepressant effect of kaempferol, a constituent of saffron (Crocus sativus) petal, in mice and rats. Pharmacologyonline 2007; 2:367-370.
12. Hosseinzadeh H, Ghenaati J. Evaluation of the antitussive effect of stigma and petals of saffron (Crocus sativus) and its components, safranal and crocin in guinea pigs. Fitoterapia 2006; 77:446-448.
13. Hosseinzadeh H, Talebzadeh F. Anticonvulsant evaluation of safranal and crocin from Crocus sativus in mice. Fitoterapia 2005; 76:722-724.
14. Hosseinzadeh H, Sadeghnia H. Protective effect of safranal on pentylenetetrazol-induced seizures in the rat: involvement of GABAergic and opioids systems. Phytomedicine 2007; 14:256-262.
15. Ayatollahi H, Javan AO, Khajedaluee M, Shahroodian M, Hosseinzadeh H. Effect of Crocus sativus L. (saffron) on coagulation and anticoagulation systems in healthy volunteers. Phytother Res 2014; 28:539-543.
16. Mousavi B, Bathaie SZ, Fadai F, Ashtari Z. Safety evaluation of saffron stigma (Crocus sativus L.) aqueous extract and crocin in patients with schizophrenia. Avicenna J Phytomed 2015; 5:413-419.
17. Ziaee T, Razavi BM, Hosseinzadeh H. Saffron reduced toxic effects of its constituent, safranal, in acute and subacute toxicities in rats. Jundishapur J Nat Pharm Prod 2014; 9:3-8.
18. HosseinZadeh H, Shakib SS, Sameni AK, Taghiabadi E. Acute and subacute toxicity of safranal, a constituent of saffron, in mice and rats. Iran J Pharm Res 2013; 12:93-99.
19.Mohajeri D, Mousavi G, Mesgari M, Doustar Y, Khayat Nouri M. Subacute toxicity of Crocus sativus L. (saffron) stigma ethanolic extract in rats. Am J Pharmacol Toxicol 2007; 2:189-193.
20.Eaton DL, Gilbert SG. Principles of Toxicology. In: Kilassen CD, Watkins III Jb, editors. Casarett & Doull,s Essentials of Toxicology. 3rd ed, New York: McGraw-Hill; 2015. p. 16-18.
21.Hosseinzadeh H, Shariaty VM, Sameni AK, Vahabzadeh M. Acute and sub-acute toxicity of crocin, a constituent of Crocus sativus L (saffron), in mice and rats. Pharmacologyonline 2010; 2: 943-951.
22.Karimi G, Taiebi N, Hosseinzadeh H, Shirzad F. Evaluation of subacute toxicity of aqueous extract of Crocus sativus L. stigma and petal in rats. J Medicina Plants 2004; 4:29-35.
23. Khayatnouri M, Safavi S, Safarmashaei S, Babazadeh D, Mikailpourardabili B. The effect of saffron orally administration on spermatogenesis index in rat. Adv Environ Biol 2011; 5:1514-1521.
24.Taheri F, Bathaie SZ, Ashrafi M, Ghasemi E. Assessment of crocin toxicity on the rat liver. Modares J Med Sci Pathobiol 2014; 17:67-79.
25.Riahi-Zanjani B, Balali-Mood M, Mohammadi E, Badie-Bostan H, Memar B, Karimi G. Safranal as a safe compound to mice immune system. Avicenna J Phytomed 2015; 5:441-449.
26. Muosa F, AL-Rekabi K, Askar SJ, and Yousif EH. Evaluation of the toxic effect of ethanolic extract of saffron in male mice after subchronic exposure. Donnish J Pharm Pharmacol 2015; 1:1-7.
27. Amin B, Feriz HM, Hariri AT, Meybodi NT, Hosseinzadeh H. Protective effects of the aqueous extract of Crocus sativus against ethylene glycol induced nephrolithiasis in rats. EXCLI J 2015; 14:411-422.
28.Hosseinzadeh H, Abootorabi A, Sadeghnia HR. Protective effect of Crocus sativus stigma extract and crocin (trans-crocin 4) on methyl methanesulfonate–induced DNA damage in mice organs. DNA Cell Biol 2008; 27:657-664.
29. Rogers JM. Developmental Toxicology. In: Kilassen CD, Watkins III Jb, editors. Casarett & Doull,s Essentials of Toxicology. 3rd ed, New York: McGraw-Hill; 2015. p. 150-151.
30.Taloubi L, Rhouda H, Belahcen A, Smires N, Thimou A, Mdaghri AA. An overview of plants causing teratogenicity: Fenugreek (Trigonella foenum graecum). Int J Pharm Sci Res. 2013; 514:516.
31. Wu M, Hu Y, Ali Z, Khan IA, Verlangeiri A, Dasmahapatra AK. Teratogenic effects of blue cohosh (Caulophyllum thalictroides) in Japanese medaka (Oryzias latipes) are probably mediated through GATA2/EDN1 signaling pathway. Chemical Res Toxicol 2010; 23:1405-1416.
32. Zeynali F, Dashti MH, Anvari M, Hosseini SM, Miresmaeili SM. Studying teratogenic an abortificant effects of different doses of saffron (Crocus sativus) decoction in whole gestational period and the 3rd trimester of gestational period in mice. Int J Reprod Biomed 2009; 7.
33. Edamula R, Deecaraman M, Kumar DS, Krishnamurthy H, Latha M. Prenatal developmental toxicity of crocus sativus (saffron) in wistar rats. Int J Pharmacol Toxicol 2014; 2:46-49.
34. Moallem SA, Afshar M, Etemad L, Razavi BM, Hosseinzadeh H. Evaluation of teratogenic effects of crocin and safranal, active ingredients of saffron, in mice. Toxicol Ind Health 2013; 32:285-291.
35. Martin G, Goh E, Neff A. Evaluation of the developmental toxicity of crocetin on Xenopus. Food Chem Toxicol 2002; 40:959-964.
36. Modaghegh M-H, Shahabian M, Esmaeili H-A, Rajbai O, Hosseinzadeh H. Safety evaluation of saffron (Crocus sativus) tablets in healthy volunteers. Phytomedicine 2008; 15:1032-1037.
37. Mohamadpour AH, Ayati Z, Parizadeh MR, Rajbai O, Hosseinzadeh H. Safety evaluation of crocin (a constituent of saffron) tablets in healthy volunteers. Iran J Basic Medical Sci 2013; 16:39-46.
38. Ajam M, Reyhani T, Roshanravan V, Zare Z. Increased miscarriage rate in female farmers working in saffron fields: a possible effect of saffron toxicity. Asia Pac J Med Toxicol. 2014; 3:73-75.
39. Sadraei H, Ghannadi A, Takei-bavani M. Effects of Zataria multiflora and Carum carvi essential oils and hydroalcoholic extracts of Passiflora incarnata, Berberis integerrima and Crocus sativus on rat isolated uterus contractions. Int J Aromather 2003; 13:121-127.
40. Inoue E, Shimizu Y, Shoji M, Tsuchida H, Sano Y, Ito C. Pharmacological properties of N-095, a drug containing red ginseng, polygala root, saffron, antelope horn and aloe wood. Am J Chin Med 2005; 33:49-60.
41. Akhondzadeh S, Tahmacebi‐Pour N, Noorbala AA, Amini H, Fallah‐Pour H, Jamshidi AH, et al.Crocus sativus L. in the treatment of mild to moderate depression: a double‐blind, randomized and placebo‐controlled trial. Phytother Res 2005; 19:148-151.
42. Akhondzadeh S, Sabet MS, Harirchian MH, Togha M, Cheraghmakani H, Razeghi S, et al. A 22-week, multicenter, randomized, double-blind controlled trial of Crocus sativus in the treatment of mild-to-moderate Alzheimer’s disease. Psychopharmacology 2010; 207:637-643.
43. Akhondzadeh S, Sabet MS, Harirchian M, Togha M, Cheraghmakani H, Razeghi S, et al. Saffron in the treatment of patients with mild to moderate Alzheimer’s disease: a 16‐week, randomized and placebo‐controlled trial. J Clin Pharm Ther 2010; 35:581-588.
44. Mansoori P, Akhondzadeh S, Raisi F, Ghaeli P, Jamshidi A, Nasehi A, et al. A randomized, double-blind, placebo-controlled study of safety of the adjunctive saffron on sexual dysfunction induced by a selective serotonin reuptake inhibitor. J Med Plants 2011; 1:121-130.
45. Shahmansouri N, Farokhnia M, Abbasi S-H, Kassaian SE, Tafti A-AN, Gougol A, 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 Affec Disord 2014; 155:216-222.
46. Basti AA, Moshiri E, Noorbala A-A, Jamshidi A-H, 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; 31:439-442.
47. Moshiri E, Basti AA, Noorbala A-A, Jamshidi A-H, Abbasi SH, Akhondzadeh S. Crocus sativus L.(petal) in the treatment of mild-to-moderate depression: A double-blind, randomized and placebo-controlled trial. Phytomedicine 2006; 13:607-611.
48. Noorbala A, Akhondzadeh S, Tahmacebi-Pour N, Jamshidi A. 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; 97:281-284.
49. Akhondzadeh S, Fallah-Pour H, Afkham K, Jamshidi A-H, Khalighi-Cigaroudi F. Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression: a pilot double-blind randomized trial [ISRCTN45683816]. BMC Complement Altern Med 2004; 4:12.
50. Fadai F, Mousavi B, Ashtari Z, Ali BN, Farhang S, Hashempour S, et al. Saffron aqueous extract prevents metabolic syndrome in patients with schizophrenia on olanzapine treatment: a randomized triple blind placebo controlled study. Pharmacopsychiatry 2014; 47:156-161.
51. Mousavi B, Fadai F, Ashtari Z, Hashempour S, Shahhamzei N, Heidarzadeh H. Safety evaluation of saffron stigma (Crocus sativus L.) aqueous extract and crocin in patients with schizophrenia. Avicenna J Phytomed 2015; 5: 413-419.
52. Ahmadi S, Azhari S, Jafarzadeh H, Rakhshandeh J, R. M. The effect of oral capsules of saffron on anxiety and fatigue during the first stage of labor. J Shahid Sadoughi Univ Med Sci 2015; 23:1915-1926.
53. Ahmadi S, Azhari S, Rakhshandeh J, Jafarzadeh H, R. M. Effect of saffron oral capsule on pain intensity active phase of the first stage of labor. IJOGI 2014; 17:1-10.
54. Milajerdi A, Djafarian K, Hosseini B. The toxicity of saffron (Crocus satious L.) and its constituents against normal and cancer cells. JNIM 2016; 3;23-32.
55. Abdullaev FI. Cancer chemopreventive and tumoricidal properties of saffron (Crocus sativus L.). Exp Biol Med 2002; 227:20-25.
56. Salomi M, Nair SC, Panikkar K. Inhibitory effects of Nigella sativa and saffron (Crocus sativus) on chemical carcinogenesis in mice. Nutr Cancer. 1991;16:67-72.
57. Bathaie SZ, Miri H, Mohagheghi M-A, Mokhtari-Dizaji M, Shahbazfar A-A, Hasanzadeh H. Saffron aqueous extract inhibits the chemically-induced gastric cancer progression in the Wistar albino rat. Iran J Basic Med Sci 2013; 16:26-38.
58. El Daly E. Protective effect of cysteine and vitamin E, Crocus sativus and Nigella sativa extracts on cisplatin-induced toxicity in rats. J pharm Belg 1997; 53:87-93.
59. Premkumar K, Abraham SK, Santhiya S, Gopinath P, Ramesh A. Inhibition of genotoxicity by saffron (Crocus sativus L.) in mice. Drug Chem Toxicol 2001; 24:421-428.
60. Trujillo-Jiménez F, García-López P, Garcia-Carranca A, Abdullaev FI. Effect of saffron on the viability of normal and malignant human cells in vitro. Acta Hortic 2004:463-470.
61. 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; 6:309-314.
62. Mousavi SH, Tavakkol-Afshari J, Brook A, Jafari-Anarkooli I. Role of caspases and Bax protein in saffron-induced apoptosis in MCF-7 cells. Food Chemical Toxicol 2009; 47:1909-1913.
63. Dhar A, Mehta S, Dhar G, Dhar K, Banerjee S, Van Veldhuizen P, et al. Crocetin inhibits pancreatic cancer cell proliferation and tumor progression in a xenograft mouse model. Mol Cancer Ther 2009; 8:315-323.
64. Aung HH, Wang CZ, Ni M, Fishbein A, Mehendale SR, Xie JT, et al. Crocin from Crocus sativus possesses significant anti-proliferation effects on human colorectal cancer cells. Exp Oncol 2007; 29:175-180.
65. Garc-Olmo DC, Riese HH, Escribano J, Ontañón J, Fernandez JA, Atiénzar M, et al. Effects of long-term treatment of colon adenocarcinoma with crocin, a carotenoid from saffron (Crocus sativus L.): an experimental study in the rat. Nutr Cancer 1999; 35:120-126.
66. Abdullaev F, Riveron-Negrete L, Caballero-Ortega H, Hernández JM, Perez-Lopez I, Pereda-Miranda R, et al. Use of in vitro assays to assess the potential antigenotoxic and cytotoxic effects of saffron (Crocus sativus L.). Toxicol In Vitro 2003; 17:731-736.
67. Ozaki A, Kitano M, Furusawa N, Yamaguchi H, Kuroda K, Endo G. Genotoxicity of gardenia yellow and its components. Food Chem Toxicol 2002; 40:1603-1610.
68. Hosseinzadeh H, Sadeghnia HR. Effect of safranal, a constituent of Crocus sativus (saffron), on methyl methanesulfonate (MMS)-induced DNA damage in mouse organs: An alkaline single-cell gel electrophoresis (comet) assay. DNA Cell Biol 2007; 26:841-846.
69. Premkumar K, Abraham SK, Santhiya ST, Gopinath PM, Ramesh A. Inhibition of genotoxicity by saffron (Crocus sativus L.) in mice. Drug Chem Toxicol 2001; 24:421-428.
70. Premkumar K, Thirunavukkarasu C, Abraham SK, Santhiya ST, Ramesh A. Protective effect of saffron (Crocus sativus L.) aqueous extract against genetic damage induced by anti-tumor agents in mice. Hum Exp Toxicol 2006; 25:79-84.
71. Hariri AT, Moallem SA, Mahmoudi M, Hosseinzadeh H. The effect of crocin and safranal, constituents of saffron, against subacute effect of diazinon on hematological and genotoxicity indices in rats. Phytomedicine 2011; 18:499-504.
72. Chang WC, Lin YL, Lee MJ, Shiow SJ, Wang CJ. Inhibitory effect of crocetin on benzo(a)pyrene genotoxicity and neoplastic transformation in C3HIOT1/2 cells. Anticancer Res 1996; 16:3603-3608.