The effects of Crocus sativus (saffron) and its constituents on nervous system: A review

Document Type: Review Article


1 Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran

2 Neurogenic Inflammation Research Center and Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Postal Code 9177948564, Iran

3 Neurocognitive Research Center and Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Postal Code 9177948564, Iran

4 Department of Physiology and Pharmacology, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran

5 Center of Toxicology Science and Research, Division of Morphology, Medical School, University of Crete, Heraklion, Crete, Greece


Saffron or Crocus sativus L. (C. sativus) has been widely used as a medicinal plant to promote human health, especially in Asia. The main components of saffron are crocin, picrocrocin and safranal. The median lethal doses (LD50) of C. sativus are 200 mg/ml and 20.7 g/kg in vitro and in animal studies, respectively. 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. Therefore, in the present article, the effects of C. sativus and its constituents on the nervous system and the possible underlying mechanisms are reviewed. Our literature review showed that C. sativus and its components can be considered as promising agents in the treatment of nervous system disorders.


Main Subjects

Abdullaev F. 1993. Biological effects of saffron. BioFactors (Oxford, England), 4:83-86

Abe K,Saito H. 2000. Effects of saffron extract and its constituent crocin on learning behaviour and long-term potentiation.Phytother Res, 14: 149–152.

Abe K, Sugiura M, Yamaguchi S, Shoyama Y, Saito H. 1999.Saffron extract prevents acetaldehyde-induced inhibition of long-term potentiation in the rat dentate gyrus in vivo. Brain Res, 851: 287–289.

Agha‐Hosseini M, Kashani L, Aleyaseen A, Ghoreishi A, Rahmanpour H, Zarrinara A, Akhondzadeh S. 2008. Crocus sativus L.(saffron) in the treatment of premenstrual syndrome: a double‐blind, randomised and placebo‐controlled trial. BJOG: Int J Gynaecol Obstet, 115:515-519

Ahmad AS, Ansari MA, Ahmad M, Saleem S, Yousuf S, Hoda MN, Islam F. 2005. Neuroprotection by crocetin in a hemi-parkinsonian rat model.PharmacolBiochemBehav, 81:805-813.

Akhondzadeh Basti A, Moshiri E, Noorbala AA, Jamshidi AH, Abbasi SH, Akhondzadeh S. 2007. 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, 31:439-442.

Akhondzadeh S, Fallah-Pour H, Afkham K, Jamshidi A-H, Khalighi-Cigaroudi F. 2004. Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression: a pilot double-blind randomized trial. BMC Complement Altern Med,4:12.

Akhondzadeh S, Sabet MS, Harirchian M, Togha M, Cheraghmakani H, Razeghi S, Hejazi SS, Yousefi M, Alimardani R, Jamshidi A. 2010a. Saffron in the treatment of patients with mild to moderate Alzheimer’s disease: a 16‐week, randomized and placebo‐controlled trial. J Clin Pharm Therapeut, 35:581-588.

Akhondzadeh S, Sabet MS, Harirchian MH, Togha M, Cheraghmakani H, Razeghi S, Hejazi SS, Yousefi MH, Alimardani R, Jamshidi A. 2010b. A 22-week, multicenter, randomized, double-blind controlled trial of Crocus sativus in the treatment of mild-to-moderate Alzheimer’s disease. Psychopharmacology, 207:637-643.

Akhondzadeh S, Tahmacebi‐Pour N, Noorbala AA, Amini H, Fallah‐Pour H, Jamshidi AH, Khani M. 2005. Crocus sativus L. in the treatment of mild to moderate depression: a double‐blind, randomized and placebo‐controlled trial. Phytother Res, 19:148-151.

Alonso Gl, Salinas MR, Garijo J, Sánchez‐Fernández MA. 2001. Composition of crocins and picrocrocin from Spanish saffron (Crocus sativus L.). JFood Quality, 24:219-233.

Amin B, Hosseinzadeh H. 2012. Evaluation of aqueous and ethanolic extracts of saffron, Crocus sativus L., and its constituents, safranal and crocin in allodynia and hyperalgesia induced by chronic constriction injury model of neuropathic pain in rats. Fitoterapia, 83:888-895.

Antony JM, van Marle G, Opii W, Butterfield DA, Mallet F,Yong VW, Wallace JL, Deacon RM, Warren K, Power C. 2004. Human endogenous retrovirus glycoprotein-mediated induction of redox reactants causes oligodendrocyte death and demyelination. Nat Neurosci. 7: 1088–1095.

Asai A, Nakano T, Takahashi M, Nagao A. 2005. Orally administered crocetin and crocins are absorbed into blood plasma as crocetin and its glucuronide conjugates in mice. J Agric  Food Chem, 53:7302-7306

Assimopoulou A, Sinakos Z, Papageorgiou V. 2005. Radical scavenging activity of Crocus sativus L. extract and its bioactive constituents. Phytother Res, 19:997-1000

Bathaie SZ, Mousavi SZ. 2010. New applications and mechanisms of action of saffron and its important ingredients. Crit Rev Food Sci Nutr, 50:761-786.

Barnett MH, Prineas JW. 2004. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol, 55: 458–468

Behl C, Lezoualc'h F, Trapp T, Widmann M, Skutella T, Holsboer F. 1997. Glucocorticoids enhance oxidative stress-induced cell death in hippocampal neurons in vitro. Endocrinology, 138: 101–106.

Bhargava V. 2011. Medicinal uses and pharmacological properties of Crocus sativus Linn (Saffron). Int J Pharmacy Pharmaceutical Science, 3:22-26

Bie XD, Chen YQ, Zheng XS, Dai HB .2011. The role of crocetin in protection following cerebral contusion and in the enhancement of angiogenesis in rats. Fitoterapia, 82:997–1002.

Bieschke J, Zhang Q, Powers ET, Lerner RA, Kelly JW. 2005. Oxidative metabolites accelerate Alzheimer's amyloidogenesis by a two-step mechanism, eliminating the requirement for nucleation. Biochemistry, 44: 4977-4983.

Boskabady MH, Rahbardar MG, Nemati H, Esmaeilzadeh M. 2010. Inhibitory effect of Crocus sativus (saffron) on histamine (H1) receptors of guinea pig tracheal chains. Die Pharmazie Int J Pharm Sci, 65:300-305.

Cestari V and Castellano C. 1997. “MK-801 potentiates morphine-induced impairment of memory consolidation in mice:involvement of dopaminergic mechanisms,” Psychopharma-cology, 133, :1–6.

Christensen, T.2005. Association of human endogenous retroviruses with multiple sclerosis and possible interactions with herpes viruses. Rev Med Virol, 15: 179–211.

Cryan JF, Lucki I. 2000. Antidepressant-like behavioral effects mediated by 5-hydroxytryptamine2C receptors. J Pharmacol Exp Therapeut, 295:1120-1126.

Deslauriers AM, Afkhami-Goli A, Paul AM, Bhat RK, Acharjee S, Ellestad KK, Noorbakhsh F, Michalak M, Power C. 2011. Neuroinflammation and endoplasmic reticulum stress are coregulated by crocin to prevent demyelination and neurodegeneration. J Immunol, 87:4788-99.

Dris R, Jain SM. 2004. Production practices and quality assessment of food crops.2004. Volume 1 Preharvest Practice. Dris, Ramdane, Jain, S. Mohan (Eds.) Springer.

Ebrahim-Habibi MB, Amininasab M, Ebrahim-Habibi A, Sabbaghian M, Nemat-Gorgani M. 2010. Fibrillation of alpha-lactalbumin: effect of crocin and safranal, two natural small molecules from Crocus sativus. Biopolymers, 93:854–865.

Ettehadi Hosseinali, Seyedeh Nargesolsadat Mojabi, Mina Ranjbaran, Jamal Shams, Hedayat Sahraei, Mahdi Hedayati, and Farzad A. 2013. Aqueous Extract of Saffron (Crocus sativus) Increases Brain Dopamine and Glutamate Concentrations in Rats. J Behav Brain Sci, 3:315-319. 

Escribano J, Alonso G-L, Coca-Prados M, Fernández J-A. 1996. Crocin, safranal and picrocrocin from saffron (Crocus sativus L.) inhibit the growth of human cancer cells in vitro. Cancer letters, 100:23-30.

Farahmand SK, Samini F, Samini M, Samarghandian S. 2013. Safranal ameliorates antioxidant enzymes and suppresses lipid peroxidation and nitric oxide formation in aged male rat liver. Biogerontology, 14: 63-71.

Fatehi M, Rashidabady T, Fatehi-Hassanabad Z. 2003. Effects of Crocus sativus petals’ extract on rat blood pressure and on responses induced by electrical field stimulation in the rat isolated vas deferens and guinea-pig ileum. J ethnopharmacology, 84:199-203

Fernández J-A, Pandalai S. 2004. Biology, biotechnology and biomedicine of saffron. Recent Res Devel Plant Sci, 2:127-159

Geromichalos GD, Lamari FN, Papandreou MA, Trafalis DT, Margarity M, Papageorgiou A, Sinakos Z. 2012. Saffron as a source of novel acetylcholinesterase inhibitors: molecular docking and in vitro enzymatic studies. J Agric Food Chem, 60:6131-6138.

Ghadami MR and Pourmotabbed A.  2009. The effect of crocin on scopolamine induced spatial learning and memory deficits in rats. Physiol Pharmacol, 12:287–295.

Ghadrdoost B, Vafaei AA, Rashidy-Pour A, Hajisoltani R, Bandegi AR, Motamedi F, Haghighi S, Sameni HR, Pahlvan S. 2011. Protective effects of saffron extract and its active constituent crocin against oxidative stress and spatial learning and memory deficits induced by chronic stress in rats. Eur J Pharmacol, 667:222-229.

Ghoshooni H, Daryaafzoon M, Sadeghi-Gharjehdagi S, Zardooz H, Sahraei H, Tehrani SP, et al. 2011. Saffron (Crocus sativus) ethanolic extract and its constituent, safranal, inhibits morphine-induced place preference in mice. Pak J Biol Sci, 14:939-944.

Gregory MJ, Menary RC, Davies NW. 2005. Effect of drying temperature and air flow on the production and retention of secondary metabolites in saffron. JAgric Food Chem, 53:5969-5975.

Haghighizad H, Pourmotabbed A, Sahraei H. 2008. Protective effect of Saffron extract on morphine-induced inhibition of spatial learning and memory in rat. Physiol Pharmacol, 12: 170–179.

Horobin RW, Kiernan JA, Commission BS. 2002. Conn's biological stains: a handbook of dyes, stains and fluorochromes for use in biology and medicine. Biological Stain Commission.

Hosseinzadeh H, Jahanian Z. 2010. Effect of Crocus sativus L. (saffron) Stigma and  its Constituents,  Crocin  and  Safranal,  on Morphine  Withdrawal  Syndrome  in  Mice. Phytother Res, 24: 726-730.

Hosseinzadeh H, Karimi G, Niapoor M. 2004. Antidepressant  effect  of  Crocus  sativus  L. stigma  extracts  and  their  constituents, crocin and safranal, in  mice. Acta Hort, 650: 435-45.

Hosseinzadeh H, Motamedshariaty V, Hadizadeh F. 2007. Antidepressant effect of kaempferol, a constituent of saffron (Crocus sativus) petal, in mice and rats. Pharmacologyonline, 2:367-370.

Hosseinzadeh H, Sadeghnia, HR. 2005. Safranal, a constituent of Crocus sativus (saffron), attenuated cerebral ischemia induced oxidative damage in rat hippocampus. J PharmPharm Sci, 8, 394–399.

Hosseinzadeh H, Sadeghnia HR, Rahimi A .2008b. Effect of safranal on extracellular hippocampal levels of glutamate and aspartate during kainic acid treatment in anesthetized rats. Planta Med, 74:1441–1445.

Hosseinzadeh H, Talebzadeh F. 2005. Anticonvulsant evaluation of safranal and crocin from Crocus sativus in mice. Fitoterapia, 76:722-724.

Hosseinzadeh H, ziaee T, sadeghi A. 2008. The effect of saffron, crocus sativus stigma, extract and its constituents, safranal and crocin on sexual behaviors in normal male rats. Phytomedicine, 15:491–495.

Hosseinzadeh H, Sadeghnia HR. 2007. Protective effect of safranal on pentylenetetrazol-induced seizures in the rat: involvement of GABAergic and opioids systems. Phytomedicine, 14, 256-62.

Hoyle CH, Burnstock G. 1991. ATP receptors and their physiological roles. Adenosine in the Nervous System:43-76.

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

Izquierdo C. Da Cunha, Rosat R, Jerusalinsky D, Ferreira MBC and Medina JH.1992. Neurotransmitter receptors involved in post-training memory processing by the amygdala, medial septum, and hippocampus of the rat. Behav Neur Biol, 58: 16–26.

Karimi GR, Hosseinzadeh H, KHALEGH PP. 2001. Study of antidepressant effect of aqueous and ethanolic extract of Crocus sativus in mice. Iran J Basic Med Sci, 4: 11-15.

Karrer P, Benz F, Morf R, Raudnitz H, Stoll M, Takahashi T. 1932. Pflanzenfarbstoffe XLVI. Konstitution des Crocetins und Bixins. Synthese des Perhydro‐norbixins. Helvetica Chimica Acta, 15:1399-1419.

Khalili M, Hamzeh F. 2010. Effects of active constituents of Crocus sativus L., crocin on streptozocin-induced model of sporadic Alzheimer's disease in male rats. Iran Biomed J, 14:59.

Khalili M, Kiasalari Z, Rahmati B, Narenjkar J. 2010. Behavioral and Histological Analysis of Crocus Sativus Effect in Intracerebroventricular Streptozotocin Model of Alzheimer Disease in Rats. Iran J Pathol, 5:27-33.

Khavandgar S, Homayoun H, Zarrindast MR.  2003. The effect of L-NAME and L-arginine on impairment of memory formation and state-dependent learning induced by morphine in mice. Psychopharmacology, 167: 291–296.

Khosravan V. 2002. Anticonvulsant effects of aqueous and ethanolic extracts of Crocus sativus L. stigmas in mice. Arc Iran Medi, 5:44.

Labak M, Foniok T, Kirk D, Rushforth D, Tomanek B, Jasiński A, Grieb P. 2010. Metabolic changes in rat brain following intracerebroventricular injections of streptozotocin: a model of sporadic Alzheimer’s disease. Brain Edema XIV, Springer.

Lannert H, Hoyer S. 1998. Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci, 112:1199.

Lechtenberg MD, Schepmann M, Niehues N, Hellenbrand B, ¨unsch W, Hensel A.  2008. Quality and functionality of saffron: quality control, species assortment and affinity of extract and isolated sa ff ron compounds to NMDA and σ 1(Sigma-1) receptors, Planta Medica, 74: 764–772.

Lechtenberg M, Schepmann D, Niehues M, Hellenbrand N, unsch WB, Hensel A.2008.Quality and functionality of saffron: quality control, species assortment and affinity of extract and isolated saffron compounds to NMDA and σ 1(Sigma-1) receptors. Plant Med, 74: 764–772,

Linardaki ZI, Orkoula MG, Kokkosis AG, Lamari FN, Margarity M .2013. Investigation of the neuroprotective action of saffron (Crocus sativus L.) in aluminumexposed adult mice through behavioral and neurobiochemical assessment. Food Chem Toxicol, 52:163–170.

Lucki I. 1997. The forced swimming test as a model for core and component behavioral effects of antidepressant drugs. Behav pharmacol, 8:523-532.

Marciniak SJ, Yun CY, Oyadomari S, Novoa I, Zhang Y, Jungreis R, Nagata K, Harding HP, Ron D. 2004. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 18: 3066.

Mashmoul M, Azlan A, Khaza'ai H, Yusof Bnm,  Noor Sm. 2013. Saffron: A natural potent antioxidant as a promising anti-obesity drug. Antioxidants, 2: 293-308.

Martin G, Goh E, Neff A. 2002. Evaluation of the developmental toxicity of crocetin on Xenopus. Food chem toxicol, 40:959-964

Melnyk JP, Wang S, Marcone MF. 2010. Chemical and biological properties of the world's most expensive spice: Saffron. Food Res Int, 43:1981-1989.

Moallem SA, Hariri AT, Mahmoudi M, Hosseinzadeh H. 2014. Effect of aqueous extract of Crocus sativus L. (saffron) stigma against subacute effect of diazinon on specific biomarkers in rats. Toxicol Ind Health, 30:141-6.

Moshiri E,  Akhondzadeh BastiA, Noorbala AA, Jamshidi AH, Abbasi SH, Akhondzadeh S. 2006. Crocus sativus L.(petal) in the treatment of mild-to-moderate depression: A double-blind, randomized and placebo-controlled trial. Phytomedicine, 13: 607-611.

Moosavi SM, Ahmadi M, Amini M, Vazirzadeh B, Sari I. 2014. The Effects of 40 and 80 mg Hydro-alcoholic Extract of Crocus Sativus in the Treatment of Mild to Moderate Depression. J Mazandaran Univ Med Sci (JMUMS) 24.

Mousavi B BS, Fadai F, Ashtari Z, Ali beige N, Farhang S, Hashempour S, Shahhamzei N, Heidarzadeh H. 2015. Safety evaluation of saffron stigma (Crocus sativus L.) aqueous extract and crocin in patients with schizophrenia. Avicenna J Phytomed, Epub.

Mousavi SH, Tayarani NZ, Parsaee H.2010. Protective effect of saffron extract and crocin on reactive oxygen species-mediated  high  glucose-induced  toxicity  in PC12 cells. Cell Mol Neurobiol, 30:185–191.

Naghibi SM,  Mahmoud Hosseini, Fatemeh Khani, Motahare Rahimi,  Farzaneh Vafaee,  Hassan Rakhshandeh,  and Azita Aghaie. 2012.  Effect of Aqueous Extract ofCrocus sativus L. on Morphine-Induced Memory Impairment. Adv Pharmacol Sci, Article ID 494367, 7 pages.

Nasri S, Sahraei H, Zardooz H. 2011.  Inhibition of pain and inflamation induced by formalin in male mice by ethanolicextract of sa ff ron (Crocus sativus) and its constituents crocin and safranal. Kowsar Med J, 15: 189–195.

Nemati H BM, Ahmadzadef Vostakolaei H. 2008. Stimulatory effect of crocus sativus (saffron) on beta2-adrenoceptors of guinea pig tracheal chains. Phytomedicine 15:1038-1045.

Nilakshi N, Gadiya RV, Abhyankar M, Champalal KD. 2011. Detailed profile of Crocus sativus.  Int J Pharma Bio Sciences, 2: 530-540.

Noorbala A, Akhondzadeh S, Tahmacebi-Pour N, Jamshidi A. 2005. 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, 97:281-284.

Ochiai T, Ohno S, Soeda S, Tanaka  H,  Shoyama  Y, Shimeno H .2004a. Crocin prevents the death of rat pheochromyctoma  (PC-12)  cells  by  its  antioxidant effects stronger than those of  α -tocopherol. Neurosci Lett, 362:61–64.

Ochiai T, Shimeno H, Mishima K, Iwasaki K, Fujiwara M, Tanaka H, Shoyama Y, Toda A, Eyanagi  R,  Soeda  S.  2007.  Protective effects  of  carotenoids  from  saffron  on neuronal  injury  in  vitro  and  in  vivo. Biochim Biophys Acta, 1770: 578-584.

Ochiai T, Soeda S, Ohno S, Tanaka H, Shoyama Y, Shimeno H. 2004. Crocin prevents the death of PC-12 cells through sphingomyelinase-ceramide signaling by increasing glutathione synthesis.Neurochem Int. 44:321-330.

Papandreou MA, Polissiou MG, Efthimiopoulos S, Cordopatis P, Margarity M, Lamari FN. 2006. Inhibitory activity on amyloid-beta aggregation and antioxidant properties of Crocus sativus stigmas extract and its crocin constituents. J Agric Food Chem, 54:8762-8768.

Papandreou MA, Tsachaki M, Efthimiopoulos S, Cordopatis P, Lamari FN, Margarity M. 2011. Memory enhancing effects of saffron in aged mice are correlated with antioxidant protection. Behav Brain Res, 219:197-204.

Pitsikas N, Zisopoulou S, Tarantilis PA, Kanakis CD, Polissiou MG, Sakellaridis N. 2007. Sakellaridis.Effects of the active constituents of Crocus sativusL., crocins on recognition and spatial rats' memory. Behav Brain Res, 83:141-146.

Pitsikas N and Sakellaridis N.  2006. Crocus sativus L. extracts antagonize memory impairments in di ff erent behavioural tasks in the rat. Behav Brain Res, 173: 112–115.

Purushothuman S, Nandasena C, Peoples CL, El Massri N, Johnstone DM, Mitrofanis J, Stone J. 2013. Saffron pre-treatment offers neuroprotection to Nigral and retinal dopaminergic cells of MPTP-Treated mice.J Parkinsons Dis, 3:77-83.

Rios J, Recio M, Giner R, Manez S. 1996. An update review of saffron and its active constituents. Phytother Res, 10:189-193.

Qi Y, Chen L, Zhang L, Liu WB, Chen XY, Yang XG. 2013. Crocin prevents retinal ischaemia/reperfusion injury-induced apoptosis in retinal ganglion cells through the PI3K/AKT signalling pathway. Exp Eye Res, 107:44-51.

Sachdeva J, Tanwar V, Golechha M, Siddiqui KM, Nag TC, Ray R, Kumari S, Arya DS. 2012. Crocus sativus L.(saffron) attenuates isoproterenol-induced myocardial injury via preserving cardiac functions and strengthening antioxidant defense system. Exper Toxicol Pathol, 64:557-564.

Sadeghnia HR, Kamkar M, Assadpour E, Boroushaki MT, Ghorbani A .2013. Protective effect of safranal, a constituent of  Crocus sativus , on quinolinic acid-induced oxidative  damage  in  rat  hippocampus.  Iran  J  Basic Med Sci, 16:73–82.

Sadeghnia H, Cortez M, Liu D, Hosseinzadeh H, Snead 3rd OC. 2008. Antiabsence effects of safranal in acute experimental seizure models: EEG and autoradiography. J Pharm  Pharm Sci, 11:1-14.

Saleem S, Ahmad M, Ahmad AS, Yousuf S, Ansari MA, Khan MB, Ishrat T, Islam F .2006. Effect of Saffron ( Crocus sativus ) on neurobehavioral and neurochemical changes in cerebral ischemia in rats. J Med Food, 9:246–253.

Shahmansouri N, Farokhnia M, Abbasi S-H, Kassaian SE, Noorbala Tafti A-A, Gougol A, Yekehtaz H, Forghani S, Mahmoodian M, Saroukhani S. 2014. 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,155:216-222.

Shati AA, Elsaid FG, Hafez EE .2011. Biochemical and molecular  aspects  of  aluminium  chloride-induced neurotoxicity in mice and the protective role  of Crocus sativus  L. extraction and honey syrup. Neuroscience, 175:66–74.

Soeda S, Ochiai T, Paopong L, Tanaka H, Shoyama Y, Shimeno H. 2001. Crocin suppresses tumor necrosis factor-alpha-induced cell death of neuronally differentiated PC-12 cells. Life Sci, 69:2887-2898.

Sugiura M, Shoyama Y, Saito H, Abe K.  1994. Crocin (crocetin di-gentiobiose ester) prevents the inhibitory effect of ethanol on long-term potentiation in the dentate gyrus in vivo. J Pharmacol Exper Therap, 271:703–707.

Sunanda BPV, RammohanB, Amitabh kumar, Kudagi BL. 2014. The effective study of aqueous extract of crocus sativus linn. In chemical induced convulsants in rats. World J Pharm Pharm Sci, 3,1175-1182.

Srivastava R, Ahmed H, Dixit R. 2010. Crocus sativus L.: a comprehensive review. Pharmacogn Rev, 4:200.

Tarantilis PA, Polissiou MG. 1997. Isolation and identification of the aroma components from saffron (Crocus sativus). J Agricul Food Chem, 45:459-462.

Vakili A, Einali MR, Bandegi AR .2013. Protective Effect of crocin against cerebral ischemia in a dose- dependent manner in a rat model of ischemic stroke. J Stroke Cerebrovasc Dis S1052–3057(12)00345-X (in press).

Veerendra Kumar M, Gupta Y. 2003. Effect of Centella asiatica on cognition and oxidative stress in an intracerebroventricular streptozotocin model of Alzheimer's disease in rats. Clin Experiment Pharmacol Physiol, 30: 336-342.

Wang Y, Han T, Zhu Y, Zheng C-J, Ming Q-L, Rahman K, Qin L-P. 2010. Antidepressant properties of bioactive fractions from the extract of Crocus sativus L. J Nat Med,64:24-30.

Winterhalter P, Straubinger M. 2000. Saffron—renewed interest in an ancient spice. Food Rev Int, 16:39-59.

Xuan B, Zhou Y-H, Li N, Min Z-D, Chiou GC. 1999. Effects of crocin analogs on ocular blood flow and retinal function.J Ocular Pharmacol Therap, 15:143-152.

Yamauchi M, Tsuruma K, Imai S, Nakanishi T, Umigai N, Shimazawa M, Hara H.2011. Crocetin prevents retinal degeneration induced by oxidative and endoplasmic reticulum stresses via inhibition of caspase activity. Eur J Pharmacol, 650: 110–119.

Zarrindast MR, Jafari-Sabet M, Rezayat M, Djahanguiri B, Rezayof A.2006. Involvement of NMDA receptors in morphine state-dependent learning in mice. Int J Neurosci, 116: 731–743,

Ziaee Toktam; Bibi Marjan Razavi ; Hossein Hosseinzadeh.  2014. Saffron  Reduced Toxic Effects of  its  Constituent,  Safranal,  in  Acute  and Subacute Toxicities in Rats. Jundishapur J Nat Pharm Prod, 9:3-8.

Zhang YY. Shoyama, M. Sugiura, Saito H.  1994. Effects of Crocus sativus L. on the ethanol-induced impairment of passive avoidance performances in mice. Biol Pharm Bulletin, 17: 217–221.

Zhang Q, Powers Et, Nieva J, Huff Me, Dendle Ma, Bieschke J, Glabe CG, Eschenmoser A, Wentworth P, Lerner Ra. 2004. Metabolite-initiated protein misfolding may trigger Alzheimer's disease. Proc Natl Acad Sci U S A, 101: 4752-4757.