Safety Evaluation of Crocin (a constituent of saffron) Tablets in Healthy Volunteers

Document Type: Original Article

Authors

1 1Pharmaceutical Research Center, Department of Pharmacodynamy and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 2Department of Pharmacodynamy and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Objective(s): Crocin is the chemical ingredient primarily responsible for the color of saffron. It has different pharmacological effects such as antioxidant, anticancer and memory improving activities. Crocin tablets were evaluated for short-term safety and tolerability in healthy adult volunteers.
Materials and Methods: The study was a randomized, double-blind, placebo-controlled design consisting of one month treatment of crocin tablets. Volunteers who fulfilled inclusion and exclusion criteria were randomized into 2 groups of 22 each (males and females) and received 20 mg crocin tablets or placebo. General measures of health were recorded during the study such as hematological, biochemical, hormonal and urinary parameters in pre and post-treatment periods.
Results: No major adverse events were reported during the trial. Crocin tablets did not change the above parameters except that it decreased amylase, mixed white blood cells and PTT in healthy volunteers after one month.
Conclusion: This clinical safety evaluation showed a relatively safe and normal profile for crocin in healthy volunteers at the given doses within the trial period.

Keywords


  1. Melnyk JP, Wang S, Marcone MF. Chemical and biological properties of the world's most expensive spice: Saffron. Food Res Int  2010; 43: 1981-1989.
2. Hosseinzadeh H, Shamsaie F, Mehri S. Antioxidant activity of aqueous and ethanolic extracts of Crocus sativus L. stigma and its bioactive constituent, crocin and safranal. Pharmacog Mag 2009; 5: 419-424.

3. Abdullaev FI. Cancer chemopreventive and tumoricidal properties of saffron (Crocus sativus L). Exp Biol Med  2002; 227: 20-25.

4. Aung HH, Wang CZ, Ni M, Fishbein A, Mehendale SR, Xie JT, Shoyama CY, Yuan CS. Crocin from Crocus sativus possesses significant anti-proliferation effects on human colorectal cancer cells. Exp Oncol 2007; 29: 175-80.

5. Hosseinzadeh H, Ziaei T. Effects of Crocus sativus stigma extract and its constituents, crocin and safranal, on intact memory and scopolamine-induced learning deficits in rats performing the Morris water maze task. J Med Plants 2006; 5: 40-50.

6. Hosseinzadeh H, Sadeghnia HR, Ghaeni FA, Motamedshariaty VS, Mohajeri SA.  Effects of saffron (Crocus sativus L.) and its active constituent, crocin, on recognition and spatial memory after chronic cerebral hypoperfusion in rats. Phytother Res 2012; 26:381-386.
7. Hosseinzadeh H, Karimi GH, Niapoor M. 2004. Antidepressant effects of Crocus sativus stigma extracts and its constituents, crocin and safranal, in mice. J Med Plants 2012; 3:48-58.

8. Zheng YQ, Liu JX, Wang JN, Xu L. 2007. Effects of crocin on reperfusion-induced oxidative/nitrative injury to cerebral microvessels after global cerebral ischemia. Brain Res 2012; 1138: 86-94.

9. Hosseinzadeh H, Sadeghnia HR, Ziaee T, Danaee A.Protective effect of aqueous saffron extract (Crocus sativus L.) and crocin, its active constituent, on renal ischemia-reperfusion-induced oxidative damage in rats. J Pharm Pharmacol Sci 2005; 387-393.

10. Goyal SN, Arora S, Sharma AK, Joshi S, Ray R, Bhatia J, Kumari S, Arya DS. Preventive effect of crocin of Crocus sativus on hemodynamic, biochemical, histopathological and ultrastuctural alterations in isoproterenol-induced cardiotoxicity in rats. Phytomedicine 2010;17: 227-32.

11. Hosseinzadeh H, Modaghegh MH, Saffari Z. Crocus sativus L. (saffron) extract and its active constituents (crocin and safranal) on ischemia-reperfusion in rat skeletal muscle. Evid Based Complement Alternat Med 2009; 6: 343–350.

12. Imenshahidi M, Hosseinzadeh H, Javadpour Y. Hypotensive effect of aqueous saffron extract       (Crocus sativus L.) and its constituents, safranal and crocin, in normotensive and hypertensive rats. Phytother Res  2010; 24: 990-4.

13. Hosseinzadeh H, Ziaee T, Sadeghi A. The effect of saffron, Crocus sativus stigma, extract and its constituents, safranal and crocin on sexual behaviors in normal male rats. Phytomedicine 2008; 15: 491-5

14. 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: 657-64.

15. Hariri AT, Moallem SA, Mahmoudi M, Memar B, Hosseinzadeh H. Sub-acute effects of diazinon on biochemical indices and specific biomarkers in rats: protective effects of crocin and safranal. Food Chem Toxicol 2010; 48: 2803-8.

16. 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.

17. Mehri S, Abnous K, Mousavi SH, Shariaty VM, Hosseinzadeh H. Neuroprotective effect of crocin on acrylamide-induced cytotoxicity in PC12 cells. Cell Mol Neurobiol 2012; 32: 227-235.

18. Hosseinzadeh H, Jahanian Z. Effect of Crocus sativus L. (saffron) stigma and its constituents, crocin and safranal, on morphine withdrawal syndrome in mice. Phytother Res 2010; 24: 726-30.

19. Imenshahidi M, Zafari H, Hosseinzadeh H. Effects of crocin on the acquisition and reinstatement of morphine-induced conditioned place preference in mice. Pharmacologyonline 2011; 1: 1007-1013.

20. Hosseinzadeh H, Shariaty MV, 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.

21. Loomis TA, Hayes AW. Loomis's Essentials of Toxicology. 1996; 208-245, California: Academic Press.

22. Mizuma H, Tanaka M, Nozaki S, Mizuno K, Tahara T, Ataka S, Sugino T, Shirai T, Kajimoto Y, Kuratsune H, Kajimoto O, Watanabe Y. Daily oral administration of crocetin attenuates physical fatigue in human subjects. Nutr Res 2009; 29: 145-50.

23. Hadizadeh F, Mohajeri SA, Seifi M.  Extraction and purification of crocin from saffron stigmas employing a simple and efficient crystallization method. Pak J Biol Sci 2010; 13: 691-698.

24. Modaghegh MH, Shahabian M, Esmaeili H, Rajbai O, Hosseinzadeh H. Safety evaluation of saffron (Crocus sativus) tablets in healthy volunteers. Phytomedicine 2008; 15: 1032-37.

25. Akhondzadeh S, Tahmacebi-Pour N, Noorbala A-A, Amini H, Fallah-Pour H, Jamshidi A-H. 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.

26. Shamsa A, Hosseinzadeh H, Molaei M, Shakeri MT, Rajabi O. Evaluation of Crocus sativus L. (saffron) on male erectile dysfunction: a pilot study.Phytomedicine 2009; 16: 690-693.

27. Akhondzadeh S, Shafiee Sabet M,           Harirchian MH, Togha M, Cheraghmakani H, Razeghi S, Hejazi SS, Yousefi MH, Alimardani R, Jamshidi A, Rezazadeh SA, Yousefi A, Zare F, Moradi A, Vossoughi A. A 22-week, multicenter, randomized, double-blind controlled trial of
Crocus sativus in the treatment of mild-to-moderate Alzheimer's disease. Psychopharmacology (Berl) 2010; 207: 637-43.

28.  Kianbakht S, Ghazavi A. Immunomodulatory effects of saffron: a randomized double-blind placebo-controlled clinical trial. Phytother Res 2011;25:1801-1805.

29. Karimi GH, Taiebi N, Hosseinzadeh H, Shirzad F. Evaluation of subacute toxicity of aqueous extract of Crocus sativus L. stigma and petal in rats.  J Med Plants 2004; 3(12) 29-35.

30. Ma SP, Liu BL, Zhou SD. et al Pharmacological studies of glycosides of saffron crocus (Crocus sativus): effects on blood coagulation, platelet aggregation, and thrombosis. Chin Trad Herbal Drugs 1999; 30: 196-198.

31. Yang L, Qian Z, Yang Y, Sheng L, Ji H, Zhou C, Kazi HA. Involvement of Ca2+ in the inhibition by crocetin of platelet activity and thrombosis formation. J Agric Food Chem 2008; 56: 9429-33 .

32. Jung WS, Chae YS, Kim DY, Seo SW, Park HJ, Bae GS, Kim TH, Oh HJ, Yun KJ, Park RK, Kim JS, Kim EC, Hwang SY, Park SJ, Song HJ. Gardenia jasminoides protects against cerulein-induced acute pancreatitis. World J Gastroenterol 2008; 14: 6188-94.

33. Asai A, Nakano T, Takahashi M, Nagao A. Orally administered crocetin and crocins are absorbed into blood plasma as crocetin and its glucuronide conjugates in mice. J Agric Food Chem 2005; 53: 302-6.

34. Xi L, Qian Z, Du P, Fu J. Pharmacokinetic properties of crocin (crocetin digentiobiose ester) following oral administration in rats. Phytomedicine 2007; 9: 633-6.

35. Sheng L, Qian Z, Zheng S, Xi L. Mechanism of hypolipidemic effect of crocin in rats: crocin inhibits pancreatic lipase. Eur J Pharmacol 2006; 543:116-22.