Pharmacological activity of saffron and crocin on dementia: a narrative review

Introduction

The Diagnostic and Statistical Manual of Mental Disorders (1) specified dementia such as Alzheimer’s disease (AD), vascular dementia (vD), frontal lobe hyperthermia, dementia with Lewy bodies, Parkinson’s disease with dementia, and Huntington’s disease with dementia. Among them AD is the most common depending on aging process. Rapid increase of dementia patients in the world becomes issue an alarm. In Japan, 7.3 million persons are speculated by 2025, and 10.2 million cases are expected by 2050 (2). This tendency is the same with the world (3). The population of dementia patients aged 60 years and over in the world was indicated the higher in Europe, United State and Japan, and lower in Asia and Africa countries (4). It might be important issue to determine the reason why such difference occurred. Epidemiological surveys confirmed that lifestyle and eating habits influence, suggesting that wine (5) or fish (6) decrease the occurrence of AD in aged people. From this evidence, the world hopes for finding of prevention method and/or preventive phytomedicines.

Several studies have shown that numerous pure compounds have anti-dementia activities (7-19), but no compounds have been clinically approved. The anti-dementia activities of saffron and crocin were well known by the protection of neuronal cell death because of strong anti-oxidation related to glutathione-dependent inhibitory mechanism, anti-inflammation activities (20) and the enhancement of learning-memory and long-term potentiation (LTP) inhibited by ethanol (21). Saffron is one of the most highly secure phytomedicine because saffron has the long food experience as spices. In fact saffron has been used longer for phytomedicine, coloring agent and spice from the thousand years (22) and is now permitted as Generally Recognized as Safe (GRAS) by the American Food And Drug Administration (FDA) (23) resulting that the most important issue for clinical use of saffron and crocin is safety without adverse effect. Therefore, saffron and crocin were administrated in healthy volunteers and confirmed their side effects (24). Stability of crocin in saffron (see Figure 1) has been discussed because the basic skeleton is polyene structure and has glycoside linkages in a molecule easily hydrolyzed by an inner β-glycosidase as shown in Figure 2. Therefore, saffron and saffron extractives should be stored under cool and dry condition (25) and confirmed the exact crocin concentration just before use in clinical trials resulted that the quality control of saffron is necessary for the constant pharmacological efficacy. Therefore, the quality control of saffron will be discussed at the first section in this review.

Figure 1 Major constituents in saffron.

Figure 2 Degradation scheme of crocin.

Since the relation between sleep disorder and depression, and dementia has been evaluated by epidemiological studies (26), clinical trials of saffron on sleep and anti-depression activity will be discussed. Recently anti-dementia activity of saffron has been investigated widely in clinical trials to confirm its efficacy. From these results the combination of saffron and other herb medicine is groped for more efficient and effective efficacy. These new prescriptions will be also discussed in this review. We present the following article in accordance with the Narrative Review reporting checklist (available at https://lcm.amegroups.com/article/view/10.21037/lcm-22-7/rc).

Methods

This article identified the publications between 1980 and 2021 on saffron and crocin in anti-dementia and neuroprotection administration via several library search engines such as PubMed, Web of Science and SciFinder for over 200 journal articles in the English language. The search strategy was indicated in Table 1.

Anti-dementia active compounds from medicinal plants

C. sativus L. (Iridaceae) was first cultivated in Greek 3,000 years ago. Currently it is cultivated in Iran, Spain, Greece and China. Saffron is obtained from only stigmas of saffron flowers resulting in too expensive herb medicine and/or spice. Typical constituents of saffron are monoterpene, safranal, monoterpene glycoside, picrocrocin and crocetin glycosides called as crocin and crocin 2, 3 and 4 as indicated in Figure 1.

Compared the long-term potentiation (LTP) blocking effect of ethanol in vivo for crocins, crocin is the most active and gradually weaken depend on sugar number and crocin 4 is negligible (21). From these results the quality control of saffron and its extractives is important in in vivo and clinical investigations. These results will be discussed in the following section.

Galantamine was originally isolated from Galanthus nivalis L and is a global anti-dementia drug for mild and moderate AD. Synthetic therapeutic drugs including galantamine for dementia are donepezil, rivastigmine and memantine.

Nakanishi reported the isolation of diterpenes and flavonoids from Ginkgo biloba L and their structure elucidation (27). Their pharmacological activities were investigated in Germany and developed to an over the counter (OTC) drug for vD prevention in Europe (28). Valeriana officinalis L. root, an OTC medicine for sleep disorders is expected to be anti-dementia active herb medicine in Europe (29,30). Polygala tenuifolia Willd. root extract is also marketed as an OTC drug for memory improvement from 2016 in Japan. Natarajan et al. and Ho et al. reported the many plants having pharmacological activities such as acetylcholine esterase and monoamine oxidase inhibition related to anti-dementia effects, anti-inflammatory activities, and learning and memory effects in animal models (7,8). In traditional Chinese medicine (TCM) and Kampo medicines the following are prescribed in formula related to dementia patients such as Acorus gramineus Aiton, Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav., Aralia cordata Thunb., Crocus sativus L., Curcuma longa L., Epimedium brevicornu Maxim., Gardenia jasminoides J. Ellis, Glycyrrhiza glabra L., Lycium chinense Mill., Magnolia officinalis Rehder & E.H.Wilson, Panax ginseng C.A.Mey., Perilla frutescens (L.) Britton, P. tenuifolia Willd., Zingiber offinale Roscoe, Salvia miltiorrhiza Bunge and Uncaria rhynchophylla (Miq.) MFiq. (31). Further survey confirmed the active constituents and their active mechanism in herb medicines prescribed in TCM, Korean and Kampo medicines as indicated in Table 2.

Furthermore, saffron will be focused on this session because saffron is also used to be a sleep accelerator (26) and an anti-depressing active herb (32). Insufficient sleep (26) and depression symptom (33) are closely related to dementia supported by epidemiological survey (34).

Stability of crocin in saffron and the quality control of saffron

Crocin seems to be unstable depend on polyenes structure in crocetin molecule suggesting that the auto-decomposition of crocins (see Figure 1) might be stimulated by storage conditions such as temperature, air, humidity and light. Saffron was stored under the combining conditions in the long-term storage period resulting that the existence of air and higher temperature promoted degradation of crocin (25). Moreover, we revealed that inner β-glucoside is stable and reactive under moisture condition to cleavage the glycoside linkage in crocetin glycosides resulting in crocin 4 via crocins 2 and 3 (25). Figure 2 indicated the degradation steps of crocin. We confirmed that the improved activity of individual crocins against the inhibition of LTP blocking activity by ethanol was proportional to the sugar numbers like crocin having four glucose in a molecule indicating the strongest improving activity and negligible activity of crocin 4 (21). This tendency was found in the biologically active natural saponins such as cardiac steroids (35), streptozotocin (36), ginsenosides (37), saikosaponins (38), and hemolytic saponins (39). From the results saffron and saffron extractives should be stored under cool and dry condition (25) until use and assessed the exact crocin concentration before use in clinical trials because crocin in saffron is changeable as discussed. Therefore, the quality control of saffron and its extractives is necessary in vitro, in vivo and clinical investigations although the nanoparticle preparation of crocin using chitosan-alginate was investigated (40). To establish the quality control of crocin in saffron we prepared anti-crocin monoclonal antibody (MAb) and set up the enzyme-linked immune sorbent assay (ELISA) system (41).

Safety of saffron and its constituent crocin

An important issue regarding medical use of saffron in humans is safety without side effects although saffron has been used for herb medicine, spice and coloring agent from the ancient years and is now approved as Generally Recognized as Safe (GRAS) by the American Food And Drug Administration (FDA) (23). In this section saffron and crocin were administrated in healthy volunteers under a double-blind, placebo-controlled study and confirmed their side effects.

Modaghegh et al. investigated the safety of saffron (200 and 400 mg tablet) during 7 days for short term safety and tolerability in healthy volunteers. In this study, saffron decreased slightly red blood cell, hemoglobin, hematocrit and platelets, and merely increased sodium, blood urea nitrogen and creatinine in blood. The authors concluded that such fluctuations were not important for clinical use although the above hematological and biochemical parameter’s differences were found (24). Ayatollahi et al. also found that saffron (200 and 400 mg tablets) are safe drug on coagulation system such as the plasma levels of fibrinogen, factor VII in healthy volunteers under a double-blind, placebo-controlled study for 1 week (42). The study of crocin tablet was administrated a randomized, double-blind, placebo-controlled design in healthy volunteers for one month. Volunteers received crocin tablet (20 mg) or placebo. During treated period biochemical, hematological, urinary and hormonal parameters were analyzed. From these results it became clear that the crocin tablet showed no major side effect except decreases of amylase, white blood cells and partial thromboplastin time (43).

We summarize the side effects of saffron and crocin. As side effects of saffron dizziness, dry mouth, fatigue, hypomania, nausea and vomiting, confusion, agitation and sedation are confirmed (44). As hematological parameter the decreases of red blood cell, hemoglobin, hematocrit and platelets, and increases of sodium, urea nitrogen and creatinine in blood and the decreases of amylase, white blood cells and partial thromboplastin time are reported. However, these side effects were same in both saffron extract and placebo groups except vomiting (45). Bloody diarrhoea, hematuria, bleeding from the nose, uterine bleeding and yellowing of the skin are occurred as side effects by the uptake of higher amount of saffron (46,47).

Clinical trials of saffron on sleep and relation between sleep and dementia

A double-blinded clinical trial randomly allowed to the saffron alcohol extractives (0.6 mg/day) or a placebo group using 21 healthy adult volunteers was investigated. The saffron extractives group significantly reduced the Pittsburgh Sleep Quality Index scores. Moreover, when compared with the placebo group a significant positive effect of saffron extractives (0.6 mg/day) on daytime dysfunction was appeared over 4 weeks in the saffron extractives group (48).

Recently Irwin indicated that sleep disorders induced inflammatory phenomenon becoming AD (26). Moreover, sleep disorder was suggested to be an important risk factor resulting in an important target for AD prevention supported by several meta-analyses and systematic reviews (49-51). Ohara et al. indicated that sleep disturbances and the hypnotic drug use increased the risk of dementia in especially aged people reported by the Hisayama epidemiological study in Fukuoka, Japan (34). The people having daily sleep durations shorter than 5.0 h have 2-fold of risk for vD and AD compared with more than 10 h cohort. This result indicated that the short sleep may influence the aging of brain and β-amyloid accumulation inducing AD. Ohara et al. also suggested that the sleep disorder induced inflammation related phenomenon and then dementia via depression (34). As we reported saffron and crocin improve non-LEM sleeping (52), the sleep time extension may be able to prevent dementia.

In the several clinical disciplines the combinations of Kampo formulas with saffron have been prescribed like that 100 mg per day of saffron was clinically used together with Chitosan, Daijyokito, Hangekobokuto, Saikokaryukotuboreito and Sansoninto which are used for sleep disorders and mental disease (53). From this evidence the combination of saffron and Kampo medicine may open a possibility of new therapeutic methodology for dementia patients.

Activities of saffron and crocin for anti-depression activities and relation between depression and dementia

The neuroprotective activities of crocin were surveyed by in vivo models, like cerebral ischemia (20), AD (54), depression (55), and memory loss (56) that are clearly associated with dementia. Depression was considered to be an omen of early stage of dementia and then confirmed as a risk factor of dementia by 2–17 years of meta-analysis. The analysis of 10,189 depression patients in the Whitehall Study in the UK showed the increase of dementia patients with the years (33). Cognitive healthy people of 4,922 around 70–80 years old were observed in 14 years resulted that the dominant number of dementia patients developed via depression (57). From above evidence it is clear that the indirect relation between saffron/crocin and dementia via sleeping and/or depression disorders was confirmed in this session.

Saffron for anti-dementia in clinical trials

The occurrence of neurodegenerative disorders such as dementia has been increasing with increased life expectancy. Among them AD is the most common, with aging the most important single risk factor and estimated to be 67.6% of dementia in the old age population. Therefore, methods to prevent dementia are needed. Among its therapeutic benefits, saffron has been reported to have neuroprotective effects (58). Data on crocin, a major constituent in saffron has shown in vivo and in vitro neuroprotective activities such as on neuronal antioxidant (59-61), anti-inflammatory (62-64), related to β-amyroid peptide, neuronal cell anti-apoptosis (65), anti-hyperlipidemia (66,67), anti-atherosclerotic (68) and anti-autophagy properties (69), resulting in reduced neuronal damage. Recently several clinical trials for AD patients as following.

Totally 54 patients of 55 years old or more old AD patients were administered saffron extractives (30 mg) or donepezil (10 mg) as a positive control in a day for 22 weeks under a double-blinded/phase II study conducting Alzheimer’s Disease Assessment Scale, Cognitive Subscale and Clinical Dementia Rating Scale and Sums of Boxes Scores compared with baseline. Adverse events (AEs) were systematically recorded. From this trial the outcome of saffron extractives was evaluated to be the same with donepezil for mild to moderate AD patients resulting in possible therapeutic effect of saffron extractives. The major adverse effect of saffron, vomiting was lower than that of donepezil (70). The double-blinded randomized clinical trial of saffron extract (30 mg per day) was performed on 46 mild to moderate AD patients for 16 weeks. The authors confirmed a significant efficacy comparing cognitive function and no side effect compared with the placebo group (71). Saffron extract (30 mg per day) capsules or memantine (20 mg per day) as a positive control was investigated as the randomized double blind parallel-group study for 68 moderate to severe AD (Mini-Mental State Examination score of 8–14) patients during one year. Patients were judged every month using Severe Cognitive Impairment Rating Scale (SCIRS) and Functional Assessment Staging (FAST). The saffron extract capsule indicated the same outcomes with memantine in decreasing cognitive phenomena without the side effect. However, the authors suggested that more large scale sample size and more long investigation terms are desired for more clear differences in the two score changes (72). Thirty five and 18 mild cognitive impairment (MCI) patients were administrated saffron alcohol extracts (125 mg/day) and placebo, respectively for one year in single-blind randomized clinical trial. Patients treated with saffron extractives improved cognitive performance judging by Mini-Mental State Examination score, event-related potential, channel electroencephalogram and magnetic resonance imaging. From these evidence the authors suggested that saffron is a good choice for treatment of mild cognitive impairment patients (73). Akhondzadeh et al. reported that 55 mild-to-moderate AD patients uptook 30 mg/day of saffron capsule or donepezil 10 mg/day for 22 weeks resulting that saffron and donepezil showed effectiveness without the side effect (70). Ayati et al. reviewed the relevant randomized clinical trials measuring AD Disease Assessment Scale-cognitive subscale and Clinical Dementia Rating Scale-Sums of Boxes in 2020 resulted that saffron significantly improved the cognitive function in AD patients compared to placebo groups and further no significant difference on daily living function and quality of life compared to the ordinary medicine (45). Recently Zandi et al. also reviewed the clinical trials of saffron for AD patients together with the mechanisms of AD onset such as neuronal oxidation, accumulation of amyloid-β and its induced inflammation, neuronal cell apoptosis, tau phosphorylation and apolipoprotein E, and the inhibiting effect of saffron and its constituents in vitro and in vivo (73).

Combination of saffron and other herb medicine for dementia

Three herbal medicines such as saffron, ginseng and Gingko biloba were prescribed together to prepare a new formula, SaiLuoTong (SLT) in China. Among them the effects of saffron were discussed previously. Lee et al. investigated that ginseng and its constituents enhanced cell survival, neurite growth, and rescued the death of neurons both in vivo and in vitro (74). Ginseng was found to increase the level of choline acetyltransferases in animal brains, indicating that they might ameliorate central cholinergic role resulting to treat dementia (75). Ginsenosides enhanced dopamine and norepinephirine in the cerebral cortex, indicating that the ginseng extract affected attention, auditive reaction time, sensory-motor function, and mental processes in healthy persons (76). Further studies have also shown positive effects on learning and memory either in aged and/or brain damaged gnawing animals (77). The effect of ginsenoside Rg1 on the proliferation of neural precursor cells may be a necessary mechanism in its cognitive enhancer and anti-aging effects (78). Recently Li et al. reviewed preclinical and clinical evidences (79). When the red ginseng steamed (4.5 g/day) was administrated for 24 weeks, behavioral symptom and learning and memory functions are promoted in moderately severe AD patients at 12 weeks resulting in the next 12-week follow-up (80). AD patients administrated high-dose (9 g/day) Korean red ginseng show significant promotions on the AD assessment scale (ADAS) and Clinical Dementia Rating scales after 12-week administration than that of placebo group (81).

On the other hand, G. biloba is also well known anti-dementia herb. Another similar product, EGb761 extract fraction of the dried leaves of G. biloba, containing flavone glycosides and diterpene lactones is an OTC drug for the prevention of vD in Europe (28).

From above evidence the SLT prescription is easily suggested to be used for prevention and/or treatment for dementia. Three hundred twenty three patients were randomly assigned to experimental groups (SLT 360 or 240 mg/day) for 26 or 52 weeks, or placebo group. Higher dose groups (360 mg/day) at week 26 were more effective than that of lower dose group (240 mg/day) resulted that SLT can be used for the treatment of vD (82).

Kai Xin San is prescribed with P. ginseng, P. tenuifolia, P. cocos and A. tatarinowii. This formula was confirmed to be used for the senile dementia (83). From the above evidences of Kai Xin San and neuronal function of saffron such as anti-neuronal cell death (20) and learning and memory activity (70), the combination of saffron and Kai Xin San was approved as Hul Tong capsule for OTC traditional Chinese medicine for prevention of dementia in Singapore in 2018.

Discussion

In the first stage we suggested that the quality control of saffron is necessary for all investigations because its major and main active constituent, crocin is sensitive against humidity concerned to β-glycosidase, auto-oxidation and high temperature. Currently, 25% of the population has been reported sleeping disorders in Japan for which saffron was prescribed in combination with Kampo medicine (53). In vivo investigation we found that saffron increased the non-REM sleeping time resulting in a sleeping promoter (52). Thus, the accumulated evidence easily suggested the clinical advantage of saffron for sleeping disorder. Sleeping and/or depression disorders apparently induced neurodegenerative illness reaching dementia. Moreover, the results discussed already indicated that saffron improves AD symptomatic in clinical trials compared with dementia drug as controls. However, the large scale and more long clinical trials are required for the development of anti-dementia and/or anti-AD drug.

The authors summarized the role of saffron and its major constituent, crocin for neurodegenerative disorders especially concerned to dementia as indicated in Figure 3. The anti-dementia activities of saffron and crocin were well known by the protection of neuronal cell death because of strong anti-oxidation related to glutathione-dependent inhibitory mechanism, anti-inflammation activities (20) and the enhancement of learning-memory via long-term potentiation (LTP) inhibited by ethanol (21) resulting in N-methyl-D-aspartate (NMDA)-receptor-reply in hippocampal cells (84). Gathered evidence saffron can be called as multifunctional herb medicine.

Figure 3 Neuronal activity of saffron, crocin on dementia/Alzheimer’s disease. Geb, gentiobiose (β-D-glucopyranosyl-(1–6)-β-D-glucopyranoside; Glc, β-D-glucopyranoside; AD, Alzheimer’s disease.

Acknowledgments

The authors sincerely thank the Faculty of Pharmacy of Nagasaki International University for providing the facilities to support this project and the Association for Health Economics Research and Social Insurance and Welfare.

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Longhua Chinese Medicine for the series “Multifunctional Saffron”. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://lcm.amegroups.com/article/view/10.21037/lcm-22-7/rc

Peer Review File: Available at https://lcm.amegroups.com/article/view/10.21037/lcm-22-7/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://lcm.amegroups.com/article/view/10.21037/lcm-22-7/coif). The series “Multifunctional Saffron” was commissioned by the editorial office without any funding or sponsorship. YS served as the unpaid Guest Editor of the series and serves as an unpaid Associate Editor-in-Chief of Longhua Chinese Medicine from September 2022 to August 2024. The authors have no other conflicts of interest to declare.

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References

1. Anonymous. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) update in 2013.
2. National Institute of Public Health. (2015). MHLW grants SYST em [in Japanese]. NIDD00. do?resrchNum=201405037A. Available online: https://mhlw-grants.niph.go.jp/niph/search
3. Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005;366:2112-7. [Crossref] [PubMed]
4. Wimo A, Winblad B, Jönsson L. The worldwide societal costs of dementia: Estimates for 2009. Alzheimers Dement 2010;6:98-103. [Crossref] [PubMed]
5. Orgogozo JM, Dartigues JF, Lafont S, et al. Wine consumption and dementia in the elderly: a prospective community study in the Bordeaux area. Rev Neurol (Paris) 1997;153:185-92. [PubMed]
6. Kalmijn S, Launer LJ, Ott A, et al. Dietary fat intake and the risk of incident dementia in the Rotterdam Study. Ann Neurol 1997;42:776-82. [Crossref] [PubMed]
7. Natarajan S, Shunmugiah KP, Kasi PD. Plants traditionally used in age-related brain disorders (dementia): an ethanopharmacological survey. Pharm Biol 2013;51:492-523. [Crossref] [PubMed]
8. Ho YS, So KF, Chang RC. Drug discovery from Chinese medicine against neurodegeneration in Alzheimer's and vascular dementia. Chin Med 2011;6:15. [Crossref] [PubMed]
9. Obara Y, Aoki T, Kusano M, et al. Beta-eudesmol induces neurite outgrowth in rat pheochromocytoma cells accompanied by an activation of mitogen-activated protein kinase. J Pharmacol Exp Ther 2002;301:803-11. [Crossref] [PubMed]
10. Lee TH, Park S, You MH, et al. A potential therapeutic effect of saikosaponin C as a novel dual-target anti-Alzheimer agent. J Neurochem 2016;136:1232-45. [Crossref] [PubMed]
11. Cho HW, Jung SY, Lee GH, et al. Neuroprotective effect of Citrus unshiu immature peel and nobiletin inhibiting hydrogen peroxide-induced oxidative stress in HT22 murine hippocampal neuronal cells. Pharmacogn Mag 2015;11:S284-9. [Crossref] [PubMed]
12. Jung HA, Min BS, Yokozawa T, et al. Anti-Alzheimer and antioxidant activities of Coptidis Rhizoma alkaloids. Biol Pharm Bull 2009;32:1433-8. [Crossref] [PubMed]
13. Lee KY, Sung SH, Kim SH, et al. Cognitive-enhancing activity of loganin isolated from Cornus officinalis in scopolamine-induced amnesic mice. Arch Pharm Res 2009;32:677-83. [Crossref] [PubMed]
14. Kim KH, Kim MA, Moon E, et al. Furostanol saponins from the rhizomes of Dioscorea japonica and their effects on NGF induction. Bioorg Med Chem Lett 2011;21:2075-8. [Crossref] [PubMed]
15. Zhu Z, Li C, Wang X, et al. 2,2',4'-trihydroxychalcone from Glycyrrhiza glabra as a new specific BACE1 inhibitor efficiently ameliorates memory impairment in mice. J Neurochem 2010;114:374-85. [Crossref] [PubMed]
16. Zhou J, Zhou L, Hou D, et al. Paeonol increases levels of cortical cytochrome oxidase and vascular actin and improves behavior in a rat model of Alzheimer's disease. Brain Res 2011;1388:141-7. [Crossref] [PubMed]
17. Huang JZ, Wu J, Xiang S, et al. Catalpol preserves neu function and attenuates the pathology of Alzheimer's disease in mice. Mol Med Rep 2016;13:491-6. [Crossref] [PubMed]
18. Oh SB, Park HR, Jang YJ, et al. Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation. Br J Pharmacol 2013;168:421-31. [Crossref] [PubMed]
19. Xian YF, Lin ZX, Mao QQ, et al. Bioassay-Guided Isolation of Neuroprotective Compounds from Uncaria rhynchophylla against Beta-Amyloid-Induced Neurotoxicity. Evid Based Complement Alternat Med 2012;2012:802625. [Crossref] [PubMed]
20. Ochiai T, Shimeno H, Mishima K, et al. Protective effects of carotenoids from saffron on neuronal injury in vitro and in vivo. Biochim Biophys Acta 2007;1770:578-84. [Crossref] [PubMed]
21. Sugiura M, Shoyama Y, Saito H, et al. Crocin (crocetin di-gentiobiose ester) prevents the inhibitory effect of ethanol on long-term potentiation in the dentate gyrus in vivo. J Pharmacol Exp Ther 1994;271:703-7. [PubMed]
22. Fujii S, Morita Y, Ohta T, et al. Saffron (Crocus sativus L.) as a valuable spice and food product: a narrative review. Longhua Chin Med 2022;5:18. [Crossref]
23. Department of Health and Human Services; Subchapter B - Food For Human Consumption (Continued); Part 182.10 - Substances Generally Recognized as Safe (GRAS). Available online: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=182
24. Modaghegh MH, Shahabian M, Esmaeili HA, et al. Safety evaluation of saffron (Crocus sativus) tablets in healthy volunteers. Phytomedicine 2008;15:1032-7. [Crossref] [PubMed]
25. Morimoto S, Umezaki Y, Shoyama Y, et al. Post-harvest degradation of carotenoid glucose esters in saffron. Planta Med 1994;60:438-40. [Crossref] [PubMed]
26. Irwin MR, Vitiello MV. Implications of sleep disturbance and inflammation for Alzheimer's disease dementia. Lancet Neurol 2019;18:296-306. [Crossref] [PubMed]
27. Nakanishi K. The ginkgolides. Pure Appl Chem 1967;14:89-113. [Crossref] [PubMed]
28. Clostre F. Ginkgo biloba extract (EGb 761). State of knowledge in the dawn of the year. Ann Pharm Fr 1999;57 Suppl 1:1S8-88. [PubMed]
29. Chen HW, He XH, Yuan R, et al. Sesquiterpenes and a monoterpenoid with acetylcholinesterase (AchE) inhibitory activity from Valeriana officinalis var. latiofolia in vitro and in vivo. Fitoterapia 2016;110:142-9. [Crossref] [PubMed]
30. Shinjyo N, Waddell G, Green J. Valerian Root in Treating Sleep Problems and Associated Disorders-A Systematic Review and Meta-Analysis. J Evid Based Integr Med 2020;25:2515690X20967323.
31. Li XJ, Zhang HY. Potential anti-dementia agents in traditional Chinese medicine. Nat Prod Commun 2009;4:877-86. [Crossref] [PubMed]
32. Kell G, Rao A, Beccaria G, et al. affron(®) a novel saffron extract (Crocus sativus L.) improves mood in healthy adults over 4 weeks in a double-blind, parallel, randomized, placebo-controlled clinical trial. Complement Ther Med 2017;33:58-64. [Crossref] [PubMed]
33. Prince M, Albanese E, Guerchet M, et al. World Alzheimer Report 2014 - Dementia and risk reduction: an analysis of protective and modifiable risk factors. Alzheimer’s Disease International (ADI) 2014; London, UK.
34. Ohara T, Honda T, Hata J, et al. Association Between Daily Sleep Duration and Risk of Dementia and Mortality in a Japanese Community. J Am Geriatr Soc 2018;66:1911-8. [Crossref] [PubMed]
35. Shimada K, Ishii N, Ohishi K, et al. Structure-activity relationship of cardiac steroids having a double linked sugar and related compounds for the inhibition of Na+, K +-adenosine triphosphatase. J Pharmacobio Dyn 1986;755-9. [Crossref] [PubMed]
36. Gunnarsson R, Berne C, Hellerström C. Cytotoxic effects of streptozotocin and N-itrosomethylurea on the pancreatic B cell with special regards to the role of nicotinamide-adenine dinucleotide. Biochem J 1974;140:487-94. [Crossref] [PubMed]
37. Takemoto Y, Ueyama T, Saito H, et al. Potentiation of nerve growth factor-mediated nerve fiber production in organ cultures of chicken embryonic ganglia by ginseng saponins: structure-activity relationship. Chem Pharm Bull (Tokyo) 1984;32:3128-33. [Crossref] [PubMed]
38. Abe H, Sakaguchi M, Konishi H, et al. The effects of saikosaponins on biological membranes. 1. The relationship between the structures of saikosaponins and haemolytic activity. Planta Med 1978;34:160-6. [Crossref] [PubMed]
39. Voutquenne L, Lavaud C, Massiot G, et al. Structure-activity relationships of haemolytic saponins. Pharm Biol 2002;40:253-62. [Crossref]
40. Rahaiee S, Shojaosadati SA, Hashemi M, et al. Improvement of crocin stability by biodegradeble nanoparticles of chitosan-alginate. Int J Biol Macromol 2015;79:423-32. [Crossref] [PubMed]
41. Xuan L, Tanaka H, Xu Y, et al. Preparation of monoclonal antibody against crocin and its characterization. Cytotechnology 1999;29:65-70. [Crossref] [PubMed]
42. Ayatollahi H, Javan AO, Khajedaluee M, et al. Effect of Crocus sativus L. (saffron) on coagulation and anticoagulation systems in healthy volunteers. Phytother Res 2014;28:539-43. [Crossref] [PubMed]
43. Moshiri M, Vahabzadeh M, Hosseinzadeh H. Clinical Applications of Saffron (Crocus sativus) and its Constituents: A Review. Drug Res (Stuttg) 2015;65:287-95. [PubMed]
44. 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;29:351-9. [Crossref] [PubMed]
45. Ayati Z, Yang G, Ayati MH, et al. Saffron for mild cognitive impairment and dementia: a systematic review and meta-analysis of randomised clinical trials. BMC Complement Med Ther 2020;20:333. [Crossref] [PubMed]
46. Mohamadpour AH, Ayati Z, Parizadeh MR, et al. Safety Evaluation of Crocin (a constituent of saffron) Tablets in Healthy Volunteers. Iran J Basic Med Sci 2013;16:39-46. [PubMed]
47. Lymperopoulou CD, Lamari FN. Saffron safety in humans: lessons from the animal and clinical studies. Med Aromat Plants 2015;4:5.
48. Nishide A, Fujita T, Nagaregawa Y, et al. Sleep Enhancement by Saffron Extract affron® in Randomized Control Trial. J Pharmacol Ther 2018;46:1407-15.
49. Shi L, Chen SJ, Ma MY, et al. Sleep disturbances increase the risk of dementia: A systematic review and meta-analysis. Sleep Med Rev 2018;40:4-16. [Crossref] [PubMed]
50. Bubu OM, Brannick M, Mortimer J, et al. Sleep, Cognitive impairment, and Alzheimer's disease: A Systematic Review and Meta-Analysis. Sleep 2017; [Crossref] [PubMed]
51. Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet 2020;396:413-46. [Crossref] [PubMed]
52. Masaki M, Aritake K, Tanaka H, et al. Crocin promotes non-rapid eye movement sleep in mice. Mol Nutr Food Res 2012;56:304-8. [Crossref] [PubMed]
53. Matsuhashi T. The effect of saffron for sleep induction. New Rem Clin 1993;42:595-7.
54. Akhondzadeh S, Sabet MS, Harirchian MH, et al. Saffron in the treatment of patients with mild to moderate Alzheimer's disease: a 16-week, randomized and placebocontrolled trial. J Clin Pharm Ther 2010;35:581-8. [Crossref] [PubMed]
55. Hausenblas HA, Saha D, Dubyak PJ, et al. Saffron (Crocus sativus L.) and major depressive disorder: a metaanalysis of randomized clinical trials. J Integr Med 2013;11:377-83. [Crossref] [PubMed]
56. Sugiura M, Shoyama Y, Saito H, et al. Crocin improves the ethanol-induced impairment of learning behaviors of mice in passive avoidance tasks. Proc Jap Acad Ser B 1995;71:319-24. [Crossref]
57. Almeida OP, Hankey GJ, Yeap BB, et al. Depression as a modifiable factor to decrease the risk of dementia. Transl Psychiatry 2017;7:e1117. [Crossref] [PubMed]
58. Bian Y, Zhao C, Lee SM. Neuroprotective Potency of Saffron Against Neuropsychiatric Diseases, Neurodegenerative Diseases, and Other Brain Disorders: From Bench to Bedside. Front Pharmacol 2020;11:579052. [Crossref] [PubMed]
59. Papandreou MA, Kanakis CD, Polissiou MG, et al. Inhibitory activity on amyloid-beta aggregation and antioxidant properties of Crocus sativus stigmas extract and its crocin constituents. J Agric Food Chem 2006;54:8762-8. [Crossref] [PubMed]
60. Chen Y, Zhang H, Tian X, et al. Antioxidant potential of crocins and ethanol extracts of Gardenia jasminoides ellis and Crocus sativus L.: A relationship investigation between antioxidant activity and crocin contents. Food Chem 2008;109:484-92. [Crossref]
61. Ochiai T, Ohno S, Soeda S, et al. Crocin prevents the death of rat pheochromyctoma (PC-12) cells by its antioxidant effects stronger than those of alpha-tocopherol. Neurosci Lett 2004;362:61-4. [Crossref] [PubMed]
62. Xu GL, Li G, Ma HP, et al. Preventive effect of in inflamed animals and in LPS-challenged RAW 264.7 cells. J Agric Food Chem 2009;57:8325-30. [Crossref] [PubMed]
63. Yarijani ZM, Pourmotabbed A, Pourmotabbed T, et al. Crocin has anti-inflammatory and protective effects in ischemia-reperfusion induced renal injuries. Iran J Basic Med Sci 2017;20:753-9. [PubMed]
64. Hussain MA, Abogresha NM, AbdelKader G, et al. Antioxidant and Anti-Inflammatory Effects of Crocin Ameliorate Doxorubicin-Induced Nephrotoxicity in Rats. Oxid Med Cell Longev 2021;2021:8841726. [Crossref] [PubMed]
65. Soeda S, Ochiai T, Shimeno H, et al. Pharmacological activities of crocin in saffron. J Nat Med 2007;61.
66. Sheng L, Qian Z, Zheng S, et al. Mechanism of hypolipidemic effect of in rats: crocin inhibits pancreatic lipase. Eur J Pharmacol 2006;543:116-22. [Crossref] [PubMed]
67. Xu GL, Yu SQ, Gong ZN, et al. Study of the effect on rat experimental hyperlipemia and the underlying mechanisms. Zhongguo Zhong Yao Za Zhi 2005;30:369-72. [PubMed]
68. Xu GL, Qian ZY, Yu SQ, et al. Evidence of against endothelial injury induced by hydrogen peroxide in vitro. J Asian Nat Prod Res 2006;8:79-85. [Crossref] [PubMed]
69. Stacchiotti A, Corsetti G. Natural Compounds and Autophagy: Allies Against Neurodegeneration. Front Cell Dev Biol 2020;8:555409. [Crossref] [PubMed]
70. Akhondzadeh S, Shafiee Sabet M, Harirchian MH, et al. A 22-week, multicenter, randomized, double-blind controlled trial of Crocus sativus in the treatment of mildto-moderate Alzheimer's disease. Psychopharmacology (Berl) 2010;207:637-43. [Crossref] [PubMed]
71. Saeedi M, Rashidy-Pour A. Association between chronic stress and Alzheimer's disease: Therapeutic effects of Saffron. Biomed Pharmacother 2021;133:110995. [Crossref] [PubMed]
72. Tsolaki M, Karathanasi E, Lazarou I, et al. Efficacy and Safety of Crocus sativus L. in Patients with Mild Cognitive Impairment: One Year Single-Blind Randomized, with Parallel Groups, Clinical Trial. J Alzheimers Dis 2016;54:129-33. [Crossref] [PubMed]
73. Zandi N, Pazoki B, Momeni Roudsari N, et al. Prospects of Saffron and its Derivatives in Alzheimer's Disease. Arch Iran Med 2021;24:233-52. [Crossref] [PubMed]
74. Steiner GZ, Yeung A, Liu JX, et al. The effect of Sailuotong (SLT) on neurocognitive and cardiovascular function in healthy adults: a randomised, double-blind, placebo controlled crossover pilot trial. BMC Complement Altern Med 2016;16:15. [Crossref] [PubMed]
75. Lee TF, Shiao YJ, Chen CF, et al. Effect of ginseng saponins on beta-amyloid-suppressed acetylcholine release from rat hippocampal slices. Planta Med 2001;67:634-7. [Crossref] [PubMed]
76. Rudakewich M, Ba F, Benishin CG. Neurotrophic and neuroprotective actions of ginsenosides Rb(1) and Rg(1). Planta Med 2001;67:533-7. [Crossref] [PubMed]
77. Yamaguchi Y, Higashi M, Kobayashi H. Effects of ginsenosides on impaired performance caused by scopolamine in rats. Eur J Pharmacol 1996;312:149-51. [Crossref] [PubMed]
78. Shen L, Zhang J. Ginsenoside Rg1 increases ischemiainduced cell proliferation and survival in the dentate gyrus of adult gerbils. Neurosci Lett 2003;344:1-4. [Crossref] [PubMed]
79. Li J, Huang Q, Chen J, et al. Neuroprotective Potentials of Panax Ginseng Against Alzheimer's Disease: A Review of Preclinical and Clinical Evidences. Front Pharmacol 2021;12:688490. [Crossref] [PubMed]
80. Heo JH, Lee ST, Chu K, et al. Heat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer's disease. Nutr Neurosci 2012;15:278-82. [Crossref] [PubMed]
81. Heo JH, Lee ST, Chu K, et al. An open-label trial of Korean red ginseng as an adjuvant treatment for cognitive impairment in patients with Alzheimer's disease. Eur J Neurol 2008;15:865-8. [Crossref] [PubMed]
82. Jia J, Wei C, Chen S, et al. Efficacy and safety of the compound Chinese medicine SaiLuoTong in vascular dementia: A randomized clinical trial. Alzheimers Dement (N Y) 2018;4:108-17. [Crossref] [PubMed]
83. Fu H, Xu Z, Zhang XL, et al. Kaixinsan, a Well-Known Chinese Herbal Prescription, for Alzheimer's Disease and Depression: A Preclinical Systematic Review. Front Neurosci 2020;13:1421. [Crossref] [PubMed]
84. Abe K, Sugiura M, Shoyama Y, et al. Crocin antagonizes ethanol inhibition of NMDA receptor-mediated responses in rat hippocampal neurons. Brain Res 1998;787:132-8. [Crossref] [PubMed]