ArticlePDF Available

Abstract and Figures

Saffron is derived from a specific portion of the flowers of Crocus sativus L. and is one of the most expensive spices in the world. Besides its use in Mediterranean, Middle Eastern, and South Asian cuisines, it also has been a part of Ayurvedic and Persian traditional healing strategies forthousands of years. Recently, human studies have emerged examining the capacity of saffron or its individual bioactive phytochemicals to ameliorate conditions and symptoms related to, for example, depression, neurodegenerative conditions, and symptoms of diabetes and cardiovascular disease. This narrative review presents a summary of human studies assessing these and other potential health benefits of saffron supplementation and highlights issues for future research.
Content may be subject to copyright.
Downloaded from http://journals.lww.com/nutritiontodayonline by xqH1N22KLExkMDKR26EGVmpQ3ebYL1uMq9OTyqtDbUgSdes4SjW7tBy+bEzKZ/JNPqSg+FC2WXv4JHx9ADJBGew3381BQwlXQFA9b4QVhKM= on 11/26/2020
Downloadedfromhttp://journals.lww.com/nutritiontodayonline by xqH1N22KLExkMDKR26EGVmpQ3ebYL1uMq9OTyqtDbUgSdes4SjW7tBy+bEzKZ/JNPqSg+FC2WXv4JHx9ADJBGew3381BQwlXQFA9b4QVhKM= on 11/26/2020
Saffron
Potential Health Benefits
Keith Singletary, PhD
Saffron is derived from a specific portion of the flowers of
Crocus sativus L. and is one of the most expensive spices in
the world. Besides its use in Mediterranean, Middle Eastern,
and South Asian cuisines, it also has been a part of Ayurve-
dic and Persian traditional healing strategies for thousands
of years. Recently, human studies have emerged examining
the capacity of saffron or its individual bioactive phytochem-
icals to ameliorate conditions and symptoms related to, for
example, depression, neurodegenerative conditions, and
symptoms of diabetes and cardiovascular disease. This narra-
tive review presents a summary of human studies assessing
these and other potential health benefits of saffron supple-
mentation and highlights issues for future research. Nutr
Today. 2020;55(6):294303
Saffron is one of the most expensive culinary herbs
and has numerous uses as a preservative, coloring
agent, food ingredient, pharmaceutical, and tradi-
tional medicine. It is derived from the dried stigmas of the
flowering perennial plant Crocus sativus L. (family Iridaceae)
that for centuries has been cultivated under specific climactic
conditions in Iran, India, and southern Europe (Figure 1). The
high cost of this spice is driven largely by the exceptionally
labor-intensive and meticulous harvesting procedures. Accord-
ing to some estimates, 225 000 stigmas from 75 000 blossoms
may be needed to produce 1 lb of saffron.
1,2
It is not surpris-
ing therefore that alternative cultivation, processing, and
harvesting procedures are being considered.
26
Saffron en-
riches several popular regional dishes such as paella in
Spain, pulao rice in India, and khoreshes (stew dishes) in
Iran and is included in a diverse array of meat, seafood, rice,
and dessert recipes. For example, saffron is a key flavoring
in French bouillabaisse, Iranian steamed saffron rice with
tahdig (chelo ba tahdig), Persian almond cake with rose wa-
ter,andIndianfrieddoughwithsaffronsyrup(Jalebi).More
than 100 biologically active compounds have been identified
in saffron, with crocin, crocetin, picrocrocin, and safranal
being major bioactives (Figure 2). To date, a variety of bio-
logical properties have been associated with these phyto-
chemicals, including antioxidation, anti-inflammation, and
antidepressant and hypolipidemic actions, mediated in part
by modulating several intracellular signaling and regulatory
pathways. Both picrocrocin and the more water-soluble
crocin are derived from the xanthophyll zeaxanthin. The
diterpenoid crocetin (8,8-diapo-8,8-carotene-dioic acid) is
formed after deglycosylation of crocin. There are at least 6
forms of crocin, with the digentobiose ester of crocetin being
the principal form in most extracts. Safranal (2,6,6-trimethyl-
1,3-cyclohexadiene-1-carboxaldehyde) is a degradation
product of picrocin. Saffron's rich red color is attributed to
crocetin esters; its bitter taste, to picrocrocin; and its distinctive
aroma, to safranal.
3,58
Its ancient uses in traditional Ayurve-
dic and Persian remedies include treatment of gastrointestinal
and genitourinary distress, asthma and respiratory conges-
tion, fever, and pain, as well as for mental and eye diseases,
to name a few.
1,913
For the past 2 decades, there has been
a steady increase in preclinical and clinical reports examining
the effects of saffron, its extracts, and individual phytochemi-
cals as potential treatments of a diverse array of health issues,
including cardiovascular disease (CVD), diabetes, psycholog-
ical and behavioral disorders, neurodegenerative conditions,
reproductive tract dysfunction, and ocular diseases.
3,6
This
narrative review gathers published information on saffron's
possible beneficial effects and provides a focused summary
on future research directions to better characterize and assess
potential emerging health benefits.
METHODS
Studies providing evidence for potential health benefits of
foods, ingredients, and plant constituents gather data from
Keith W. Singletary, PhD, is professor emeritus of nutrition in the De-
partment of Food Science and Human Nutrition at the University of
Illinois. From 2001 to 2004, he was the director of the Functional Foods
for Health Program, at the Chicago and Urbana-Champaign campuses
of the University of Illinois. Dr Singletary received bachelor and master's de-
grees in microbiology from Michigan State University and his PhD in nutri-
tional sciences from the University of Illinois. Dr Singletary's primary
research interests include molecular carcinogenesis and the potential use
of natural products in cancer chemoprevention. Dr Singletary currently re-
sides in Florida.
Funding for the preparation of this article was provided by McCormick
and Co.
The author has no conflicts of interest to disclose.
This is an open-access article distributed under the terms of the Creative
Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-
NC-ND), where it is permissible to download and share the work provided
it is properly cited. The work cannot be changed in any way or used
commercially without permission from the journal.
Correspondence: Keith Singletary, PhD, Department of Food Science
and Human Nutrition, University of Illinois at Urbana-Champaign, 905
South Goodwin Avenue, Urbana, IL (kws@illinois.edu).
Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc.
DOI: 10.1097/NT.0000000000000449
Food Science
294 Nutrition Today
®
Volume 55, Number 6, November/December 2020
a variety of scientific methods such as cell culture experiments,
animal studies, and human clinical trials. Human studies are
particularly important in determining public health recom-
mendations, especially those randomized controlled trials
testing well-characterized treatments and applying appro-
priate statistical analyses. With this in mind, a search of the
PubMed and Science Direct databases was conducted using
terms that included C. sativus, saffron, crocin, crocetin,
picrocrocin, and safranal. Full reports of English-language
publications and English-language abstracts of foreign-
language articles from peer-reviewed journals were the
primary sources of information. Although the quality of
identified studies varied considerably, all published inves-
tigations were included in this overview so that the totality
and diversity of information can be described and issues
for future research can be identified. Additional informa-
tion was gleanedfrom bibliographies withinthese sources.
Studies of saffron as a component within multi-ingredient
preparations were not included in this overview.
RESULTS
Bioavailability
The amount and form of a food ingredient or phytochemical
that is consumed, and absorbed and distributed throughout
the body in the circulation can differ substantially from the
dose and form ultimately accessible to tissues and organs of
the body. This terminal biological availability or disposition
determines in part the local effective dose and is an important
factor in understanding the physical response or lack thereof
of a food component.
On the basis of animal studies, oral intake of crocin re-
sults in its deglycosylation to crocetinby enzymes in the in-
testinal epithelium where it is rapidly absorbed by passive
transcellular diffusion. After glucuronidation in the in-
testine and liver, crocetin appears in the circulation as
monoglucuronides and diglucuronides.
12,1417
Information
on the bioavailability of saffron and its bioactive constit-
uents in humans is limited. For example, in 1 study,
18
healthy human volunteers were given a commercial saf-
fron extract (affron) at 2 doses (56 and 84 mg). The com-
position of this extract (% dry weight basis) was 3.63%
total crocins, 3.21% picrocrocin, 0.03% crocetin, and 0.04%
safranal. The mean time for crocetin to reach maximum
plasma concentration (T
max
) was 60 and 90 minutes, and
the mean maximum plasma concentration (C
max
)was
0.26 and 0.39 μg/mL, for the 56- and 84-mg doses, respec-
tively. However, crocins, picrocrocin, and safranal were
not detected in plasma in this study. In another study,
Chryssanthi et al
19
provided 4 human subjects with a cup
of saffron tea made from 200-mg dried stigmas. By 2 hours,
postconsumption plasma levels of crocetin were 1.24 to
3.67 μM. Crocetin also was examined in healthy adults
20
administered with 3 different doses of 7.5, 15, and 22.5 mg.
Crocetin was rapidly absorbed with a T
max
of 4.0 to 4.8 hours,
which is substantially faster than such values reported for
the C40 carotenoids such as carotene, lutein, or lycopene.
The C
max
increased in a dose-dependent manner between
100.9 and 297.7 ng/mL and was no longer detected by
24 hours. In future studies, the dose-dependent disposi-
tion of saffron and its constituents in target tissues and
FIGURE 1. Saffron flowers, stigmas, and powder.
Volume 55, Number 6, November/December 2020 Nutrition Today
®
295
the identity of key metabolites there need to be further
characterized.
Potential Health Benefits
The potential health benefits reported for saffron are
summarized in the Table. Considered collectively, the
quality of these human studies is not consistently high,
often due, for example, to design flaws, inadequate controls,
and limited statistical analyses. In addition, the amounts of
active components within different saffron samples are not
consistently known, which can hamper comparison of
clinical effects among trials. Unless specifically noted, the
term saffron treatment in the text refers to C. sativus stigma
powder or stigma extract (usually ethanolic or aqueous)
administered in supplemental form. Similarly, individual
constituents such as crocin or crocetin are provided as
supplements.
Psychological, Behavioral, and Neurological Effects
Saffron and major constituents were investigated as a treat-
ment of depression in nearly 2 dozen human trials. Most
trials provided 30 mg/d of a stigma extract (some as propri-
etary products such as SaffroMood, Satiereal, or affron stan-
dardized to specific crocin or safranal content). Treatment
durations were 4 to 12 weeks. One study provided crocin
alone. For patients with mild to moderate depression,
saffron significantly reduced the severity of symptoms,
compared with placebo.
2125,27,28,3941
Of note, 1 trial
41
ad-
ministered an extract of C. sativus petals and observed sig-
nificant improvement, compared with controls. Because
crocin is largely absent from petal extracts, this suggests that
portions of the C. sativus plant other than stigmas may be a
source of bioactive and possibly less expensive compounds.
Ten trials compared saffron with medications typically pre-
scribed to treat depression including the selective serotonin
FIGURE 2. Structures of saffron bioactive constituents.
296 Nutrition Today
®
Volume 55, Number 6, November/December 2020
reuptake inhibitors sertraline, fluoxetine, and citalopram,
and the tricyclic antidepressant imipramine.
2938
Saffron's ef-
fect on these patients was not statistically different than
those responses due to the medications, indicating that saf-
fron improved symptoms in a comparable way with these
antidepressant drugs.
Recent systematic reviews and meta-analyses conclude
that saffron is significantly more effective than placebo in
reducing the severity of depression and exhibits similar or
equal efficacy to antidepressants.
6974
Moreover, there
were no significant differences in adverse events between
saffron and placebo among the trials. The most commonly
reported adverse events were headache, nausea, appetite
changes, anxiety dry mouth, drowsiness, and constipation.
Although these findings from clinical trials are promising,
several methodological concerns were raised in these anal-
yses that illustrate possible reasons for any inconsistencies
in outcomes reported and why better future trials are war-
ranted. Doses administered differed by 45-fold among trials,
durations of treatments varied by 3-fold, and generally, sample
TABLE Summary of Potential Health Benefits of Saffron in Humans
Health Issue of Patients
Saffron Samples
(Doses and Durations) Outcomes Refs.
Depression Stigma extract (2830 mg/d; 612 wk)
Stigma powder (100 mg/d; 12 wk) or
crocin (30 mg/d; 8 wk)
Petal extract (30 mg/d; 6 wk)
Improved: depression symptoms
Similar efficacy vs antidepressant medications
Improved: depression symptoms
Improved: depression symptoms
2128
2938
39,40
41
Learning/memory disorder Stigma powder
Petal extract (30 mg/d; 3 wk)
Inconsistent outcomes: alertness, memory
Improved: short-term (but not long-term)
memory
42
43
Alzheimer's disease Stigma extract (30 mg/d; 412 mo) Improved: cognitive function
Similar or equal efficacy vs
cognition-enhancing medications
44
45,46
Amnesic mild cognitive
impairment
Stigma powder (12 mo) Inconsistent outcomes: cognitive function,
behavior, daily living activities duties
47
Type 2 diabetes mellitus and
prediabetes
Stigma powder (1001000 mg/d;
812 wk)
Stigma extract (1530 mg/d; 812 wk)
Crocin (15 mg/d; 3 mo)
Inconsistent effect: FBG, serum lipid profile, BP
No effect: SI, IR, HbA
1C
, anthropometric
measures, serum liver enzymes, serum
cytokines
Decreased: FBG
Inconsistent effect: lipid profile, HbA
1C
No effect: SI, IR, BP, BMI, cytokines,
liver enzymes
Decreased: FBG, HbA
1C
No effect: lipid profile, liver enzymes
4852
5357
58
Metabolic syndrome Stigma powder (100 mg/d; 12 wk)
Crocin (3060 mg/d; 68wk)
Inconsistent effect: FBG, lipid profile
Decreased: serum HSP27 antibody, serum PAB
Increased: serum leptin
No effect: BP, serum cytokines
Decreased: PAB
No effect: CRP, HSP27 antibody, FBG, lipid
profile, BP, BMI
5962
6365
Cardiovascular disease Stigma extract (30 mg/d; 8 wk)
Crocin (30 mg/d; 8 wk)
Crocetin (10 mg/d; 8 wk)
Decreased: BMI, WC, serum oxLDL
No effect: FBG, lipid profile
Decreased: oxLDL
Decreased: BMI, ICAM-1, VCAM-1, MCP-1
Increased: HDL
No effect: other blood lipids, FBG, BP
66,67
67
68
Abbreviations: BMI, body mass index; BP, blood pressure; CRP, C-reactive protein; FBG, fasting blood glucose; HbA
1C
, glycated hemoglobin; HDL,
high-density lipoprotein cholesterol; HSP, heat shock protein; ICAM, intercellular adhesion molecule; IR, insulin resistance; MCP, monocyte
chemoattractant protein; oxLDL, oxidized low-density lipoprotein cholesterol; PAB, prooxidant-antioxidant balance; SI, serum insulin;VCAM, vascular
cell adhesion molecule; WC, waist circumference.
Volume 55, Number 6, November/December 2020 Nutrition Today
®
297
size was small (averaging 21 for controls and 24 for interven-
tions). Of interest is that 1 meta-analysis examined patients'
responses to saffron depending on the specific mental health
test or measurement used. Saffron exposure significantly
improved scores when certain tests were used (Beck De-
pression Inventory and Beck Anxiety Inventory) but not
others (Hamilton Depression Rating Scale and Hamilton
Anxiety Rating Scale), suggesting that measurement test
content or quality may affect trial outcomes. The authors col-
lectively recommend numerous specific changes in trials
including larger, randomized, well-controlled designs; tests
of multiple doses (to determine optimal dose-response
range) of standardized saffron extracts for a longer dura-
tion of treatment; and additional analyses to determine
gender- and age-specific efficacy. Whether saffron is effec-
tive as an add-on to antidepressant treatment needs more
study. There is evidence that saffron dosing can reduce
anxiety symptoms in adults and youths,
22
and possibly
learning and memory shortcomings,
42,43
suggesting that
additional examination of saffron intervention on other
mood disorders and cognitive deficits in a broader age
range of subjects is warranted. Future studies also should
provide clear and consistent classification of subjects' base-
line conditions. Moreover, trials need to be conducted in
diverse global populations because most studies to date
originated in Iran and India. To better characterize potential
mechanisms of action, additional quantitation of inflammatory,
neurochemical, endocrine, and oxidative stress biomarkers in
subjects is needed.
75
In light of the current evidence, guidelines
from the Canadian Network for Mood and Anxiety Treatments
regarding use of complementary and alternative medicine
treatments recommend that saffron not be considered as a
first- or second-line treatment of depression.
76
Mechanisms by which saffron may alleviate symptoms
of human depression and cognitive deficits are poorly un-
derstood. On the basis primarily of preclinical experiments,
potential actions include antioxidant and anti-inflammatory
effects, modulation of the hypothalamus-pituitary-adrenal axis
and serotonergic processes, and neuroprotective actions.
75,77
In other recent reviews, oral intake of saffron was
shown to improve cognitive function and functional status
(community and home life, and personal care duties) for
subjects with neurodegenerative conditions such as Alzheimer's
disease (AD) and amnesic mild cognitive impairment
(MCI), which is suspected of being an early stage in neuro-
degenerative progression to dementia. Saffron was supe-
rior to placebo and demonstrated similar efficacy to anti-
AD medications such as donepezil and memantine.
78,79
Human studies have not yet clearly established the
mechanisms underlying saffron's neurological actions toward
neurodegenerative disorders. It is known in humans that the
prescribed medications memantine and donepezil can inhibit
acetylcholinesterase and antagonize N-methyl-D-aspartate ac-
tion. On the basis of animal models of AD and Parkinson's
disease, other possible mechanisms may include suppressing
reactive oxygen and nitrogen radical generation, lowering in-
flammation, lessening cellular apoptosis in specific brain re-
gions, altering cholinergic transmission, and inhibiting the
deposition and enhancing the removal of β-amyloid fibrils
in the brain.
8083
Effects on Lipid and Glucose Dysregulation
More than 20 human trials during the past decade assessed
saffron's effect on subjects exhibiting risk factors for CVD,
type 2 diabetes mellitus, and metabolic syndrome (MetS).
Doses of samples differed among studies. For extracts,
amounts given varied from 15 to 30 mg/d; for stigma pow-
der, from 100 mg/d to 1 g/d; and for crocin and crocetin,
from 15 to 30 mg/d. Most saffron treatments were given
as tablets, with the exception of 2 trials in which the pow-
der was incorporated into black tea.
48,49
The trials provided
saffron interventions for periods lasting 6 to 12 weeks.
Inconsistent improvements in fasting blood glucose
(FBG) were reported, with 6 of 14 CVD and MetS trials ob-
serving lower FBG in those provided saffron, compared
with controls. When it was measured, % HbA
1C
value was
unchanged in 4 of 5 trials. Improvement in dyslipidemia
was inconsistent as well. In 7 of 15 trials, an improvement
in at least 1 blood lipid measurement was reported, al-
though there was considerable heterogeneity when individ-
ual changes in total cholesterol, triglycerides, low-density
lipoprotein cholesterol, or high-density lipoprotein choles-
terol levels were assessed. Similarly, inconsistent outcomes
were reported in trials examining blood pressure and re-
nal and liver function. Only 3 of 12 studies detected
saffron-associated decreases in body mass index, body
weight, or waist circumference, compared with placebo.
These studies, however, were consistent in showing no
significant difference in adverse events between saffron
treatment and controls.
Recent systematic reviews and meta-analyses reached
disparate conclusions about the effect of saffron intake on
blood glucose and lipid regulation, and anthropometric
measures.
8489
It is notable that the subjects' disease status
in trials selected for examination by these systematic re-
views and meta-analyses differed. For example, whereas 1
meta-analysis selected trials with subjects with type 2 diabe-
tes mellitus and MetS, another meta-analysis chose trials
for review with subjects exhibiting diverse conditions
such as diabetes, coronary artery disease, schizophrenia,
depression, and normal health. It was suggested that
disease-specific factors may possibly contribute to outcome
variability among these reviews. Thus, it is recommended
that patients with more homogeneous stages of disease be
the focus of reviews. In the case of evaluating the effect of
saffron on blood lipid regulation, dyslipidemic patients
should be selected. In addition, a subgroup analysis of FBG
changes showed significant saffron-associated improvement
298 Nutrition Today
®
Volume 55, Number 6, November/December 2020
in trials in which treatment duration was at least 12 weeks.
85
Other issues contributing to inconsistencies in outcomes
among trials were identified as small sample sizes, variable
trial methodologies, diverse saffron materials tested, and
inconsistent measurement of other factors that influence
glucose and lipid homeostasis, such as dietary intake, body
mass index, and physical activity.
84,86
Potential mechanisms for antidiabetic benefits include
suppression of oxidative stress and inflammation, improve-
ment of pancreatic β-cell function, and modulation of insulin
signaling pathways and translocation of glucose transporter
type 4. Mechanisms for saffron's influence on dyslipidemia
and atherosclerosis may include interfering with gastrointes-
tinal tract lipases after meals, increasing serum adiponectin
levels, enhancing antioxidant and anti-inflammatory mech-
anisms, lowering blood pressure and platelet aggregation,
and modulating signaling pathways such as those involving
peroxisome proliferator-activated receptor γand heat shock
proteins.
12,9093
Additional Miscellaneous Actions
There is limited and inconclusive evidence that saffron
may help treat sexual dysfunction,
9496
certain ocular dis-
eases,
97,98
premenstrual syndrome,
99102
insomnia,
103105
and multiple sclerosis.
106108
SAFETY
Occupational allergies to saffron among saffron workers
chronically exposed to higher amounts of this spice were
observed.
109,110
Although there are anecdotal reports of al-
lergic responses to saffron in consumers, the allergic poten-
tial of saffron is likely low.
111113
Human trials that assessed
oral intake of saffron or its constituents in amounts less
than 400 mg/d showed no statistically significant differ-
ences in adverse effects, compared with controls. When
evaluated in short-term human safety trials (730 days), saf-
fron (30400 mg/d), and crocin (20 mg/d) intakes were not
associated with clinically significant changes in hematolog-
ical, biochemical, hormonal, or urinary parameters,
114116
although in 1 report, crocin dosing was associated with de-
creases in serum amylase and mixed white blood cells.
114
Recent summaries of human toxicity studies suggest that
oral administration of saffron at the maximum tolerated
dose of 1.5 g/d is recommended as safe, whereas a dose
of 5-g/kg body weight is toxic and 20-g/kg body weight
is considered lethal.
11,12,17,117
Caution in the use of supple-
mental saffron is advised for individuals with kidney and
bleeding disorders, and its use should be avoided in preg-
nancy. Specifically, doses greater than 10 g/d can lead to
genitourinary and gastrointestinal bleeding and uterine
stimulation. An abortion-inducing action of saffron was re-
ported at doses greater than 10 g/d.
11,12,17
Taking these
studies into consideration, the amounts of saffron consumed
at levels commonly used in the diet and less than 400 mg/d
are likely safe. In this regard, there are dozens of commercial
products containing saffron extract alone or in a mixture of
bioactives. Most commercial extracts provide saffron constit-
uents in amounts typically from 30 to 88 mg/capsule, which
translates to daily doses as high as 180 mg, if recommended
dosing is followed. For example, affron, a proprietary product
used in some trials, is marketed as an extract standardized by
high pressure liquid chromatography to 0.3% of a mixture of
crocin, picrocrocin, and safranal, and recommended daily
dose of 28 mg. Similarly, another product used in trials,
Satiereal, is a stigma extract containing 88 mg/capsule stan-
dardized to 0.3% safranal. SaffroMood contains 15-mg
extract/capsule, and the daily dose is 2 capsules. Nonethe-
less, to better characterize the safety of saffron intake, con-
siderably longer oral intake of saffron needs to be studied
to determine dose-associated safety related to gender, age,
andhealthstatusofconsumers.
CONCLUSIONS
To date, although the quality of many human trials is vari-
able, there is preliminary support for an emerging benefit
of saffron intake in lessening symptoms of depression.
For these studies of depression as well as for those
targeting other health conditions, there is a common need
for clinical trials to be larger, longer, and well controlled,
and to examine multiple oral doses of well-characterized,
standardized interventions. Additional human metabolic
data are clearly needed so that potential mechanisms of ac-
tion can be assessed. Furthermore, biomarkers of bioavail-
ability after saffron consumption need to be quantitated in
conjunction with health outcomes measured, so that find-
ings from multiple studies can better be compared and
interpreted. The collective assessment of higher quality sci-
entific data will better guide future recommendations re-
garding any benefits of supplemental and culinary saffron
consumption for improving mental health.
REFERENCES
1. Hosseinzadeh H. Saffron: a herbal medicine of the third millen-
nium. Jundishapur J Nat Pharm Prod. 2014;9:12.
2. Bathaie S, Farajzade A, Hoshyar R. A reviewof the chemistry and
uses of crocins and crocetin, the carotenoid natural dyes in saf-
fron, with particular emphasis on applications as colorants in-
cluding their use as biological stains. Biotechnic Histochem.
2014;89:401411.
3. Moratalla-Lopez N, Bagur M, Lorenzo C, et al. Bioactivity and
bioavailability of the major metabolites of Crocus sativus L.
flower. Molecules. 2019;24:29272950.
4. Dawalbhakta M, Telang M. Patents on therapeutical and cos-
metic applications of Crocus sativus L. and their production
through synthetic biology methods: a review. Rec Pat Biotech.
2017;11:319.
5. Ahrazem O, Rubio-Moraea A, Nebauer S, et al. Saffron: its phyto-
chemistry, developmental processes, and biotechnological pros-
pects. JAgricFoodChem. 2015;63:87518764.
Volume 55, Number 6, November/December 2020 Nutrition Today
®
299
6. Christodoulou E, Kadoglou N, Kostomitsopoulos N, Valsami G.
Saffron: a natural product with potential pharmaceutical applica-
tions. J Pharm Pharmacol. 2015;67:16341649.
7. Mykhailenko O, Kovalyov V, Goryacha O, Ivanauskas L,
Georgiyants V. Biologically active compounds and pharmaco-
logical activities of species of the genus Crocus: a review. Phyto-
chemistry. 2019;162:5689.
8. Chrysanthou A, Pouliou E, Kyriakoudi A, Tsimidou M. Sensory
threshold studies of picrocrocin, the major bitter compound of
saffron. JFoodSci. 2016;81:S180S198.
9. Hosseinzadeh H, Nassiri-Asl M. Avicenna's (Ibn Sina) the can-
non of medicine and saffron (Crocus sativus): a review. Phytother
Res. 2013;27:475483.
10. Srivastava R, Ahmed H, Dixit R, Dharamveer Saraf S. Crocus
sativus L. A comprehensive review. Pharmacogn Rev. 2010;4:
200208.
11. Schmidt M, Bettig G,Hensel A. Saffron in phytotherapy: pharma-
cology and clinical uses. Wien Med Wochenschr. 2007;157:
315319.
12. Ghaffari S, Roshanravan N. Saffron: an updated review on bio-
logical properties with special focus on cardiovascular effects.
Biomed Pharmacother. 2019;109:2127.
13. Bukhari S, Manzoor M, Dhar M. A comprehensive review of the
pharmacological potential of Crocus sativus and its bioactive
apocarotenoids. Biomed Pharmacother. 2018;98:733745.
14. Christodoulou E, Grafakou M, Skaltsa E, et al. Preparation,
chemical characterization, and determination of crocetin's phar-
macokinetics after oral and intravenous administration of saffron
(Crocus sativus L.) aqueous extract to C57/BL6J mice. JPharm
Pharmacol. 2019;71:753764.
15. Zhang Y, Fei F, Zhu X, et al. Sensitive analysis and simultaneous
assessmentof pharmacokinetic properties of crocin and crocetin
after oral administration in rats. J Chromatog B. 2017;10441045:
17.
16. 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;
53:73027306.
17. Broadhead G, Chang A, Grigg J, McCluskey P. Efficacy and
safety of saffron supplementation: current clinical findings. Crit
Rev Food Sci Nutr. 2016;56:27672776.
18. Almodovar P, Briskey D, Rao A, Prodanov M, Inarejost-Garcia A.
Bioaccessibility and pharmacokinetics of a commercial saffron
(Crocus sativus L.) extract. Evid Based Complement Altern
Med. 2020;2020:1575730. doi.org/10.1155/2020/1575730.
19. Chryssanthi D, Lamari F, Georgakopoulos C, Cardopatis P. A
new validated SPE-HPLC method for monitoring crocetin in
human plasmaapplication after saffron tea consumption.
J Pharmaceut Biomed Anal. 2011;55:563568.
20. Umigai N, Murakanik K, Ulit M, et al. The pharmacokinetic pro-
file in healthy adult human volunteers after a single oral admin-
istration. Phytomedicine. 2011;18:575578.
21. Akhondzadeh S, Talunacebi-Pour N, Noorbala A, et al. Crocus
sativus L. in the treatment of mild to moderate depression: a
double-blind, randomized and placebo-controlled trial. Phytother
Res. 2005;19:148151.
22. Lopresti A, Drummond P, Inarejos-Garcia A, Prodanov M.
affron®, a standardized extract from saffron (Crocus sativus L.)
for the treatment of youth anxiety and depressive symptoms: a
randomized, double-blind, placebo-controlled study. JAffect
Disord. 2018;232:349357.
23. 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 clini-
cal trial. Complement Ther Med. 2017;33:5864.
24. Tabeshpour J, Sobhani F, Sadjadi S, et al. A double-blind, ran-
domized, placebo-controlled trial of saffron stigma (Crocus
sativus L.) in mothers suffering from mild-to-moderate postpar-
tum depression. Phytomedicine. 2017;36:145152.
25. Jalali F, Hashemi S. The effect of saffron on depression among
recovered consumers of methamphetamine living with HIV/
AIDS. Subst Use Misuse. 2018;53:19511957.
26. Kashini L, Esalatmanesh S, Eftekhari F, et al. Efficacy of Crocus
sativus (saffron) in treatment of major depressive disorder asso-
ciated with post-menopausal hot flashes: a double-blind, ran-
domized, placebo-controlled trial. Arch Gynecol Obstet.2018;
297:717724.
27. Akhondzadeh S, Mostafavi S, Keshavarz S, et al. A placebo con-
trolled randomized clinical trial of Crocus sativus L. (saffron) on
depression and food craving among overweight women with
mild to moderate depression. JClinTher. 2019;45:134143.
10.1111/jcpt.13040.
28. Abedimanesh N, Ostradrahimi A, Bathaie S, et al. Effects of
saffron aqueous extract and its main constituent, crocin, on
health-related quality of life, depression, and sexual desire in
coronary artery disease patients: a double-blind, placebo-
controlled, randomized clinical trial. Iran Red Crescent Med J.
2017;19:e13676.
29. Akhondzadeh S, Fallah-Pour H, Afkham K, et al. Comparison of
Crocus sativus L. and imipramine on the treatment of mild to
moderate depression: a pilot double-blind randomized trial
[ISRCTN45683816]. BMC Complement Altern Med. 2004;4:12.
doi:10.1186/ 1472-6882-4-12.
30. Noorbala A, Akhdondzadeh 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:
281284.
31. BastiA,MoshiriE,NoorbalaA,etal.Comparisonofpetalof
Crocus sativus L. and fluoxetine in the treatment of depressed
patients: a pilot double-blind randomized trial. Prog Neutp
Psychopharmacol Psychiat. 2007;31:439442.
32. Shahmansouri N, Farokhnia M, Abbasi S, 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 percutaneouscoronary intervention patients.
JAffectDisord. 2014;155:216222.
33. Kashani L, Eslatmanesh S, Saedi N, et al. Comparison of saffron
versus fluoxetine in treatment of mild to moderate postpartum depres-
sion: a double-blind, randomized clinical trial. Pharmacopsychiatry.
2017;50:6468.
34. SahraianA, Jelodar S, Javid Z, et al. Study of the effects of saffron
on depression and lipid profiles: a double-blind comparative
study. Asian J Psychiat. 2016;22:174176.
35. Ghajar A, Nelshabouri S, Velayati N, et al. Crocus sativus L. ver-
sus citalopram in the treatment of major depressive disorder
with anxious distress: a double-blind, controlled clinical trial.
2017;50:152160.
36. Jelodar G, Javid Z, Jelodar S. Saffron improved depression and
reduced homocysteine level in patients with major depression:
a randomized, double-blind study. Avicenn J Phytomed.2018;
8:4350.
37. Ahmadpanah M, Ramezanshams F, Ghaleiha A, et al. Crocus
sativus L. (saffron) versus sertraline on symptoms of depression
among older people with major depressive disordersa double-
blind, randomized intervention study. Psychiat Res. 2019;282:
112613. doi.org/10.1016/j.psychres.2019.112613.
38. Lopresti A, Smith S, Hood S, Drummond P. Efficacy of a
standardised saffron extract (affron®) as an add-on to anti-
depressant medication for the treatment of persistent depressive
symptoms in adults: a randomized, double-blind, placebo-
controlled study. J Psychopharmacol. 2019;33:14151427.
39. Mazidi M, Shemshian M, Mousavi S, et al. A double-blind, ran-
domized and placebo-controlled trial of saffron (Crocus sativus
300 Nutrition Today
®
Volume 55, Number 6, November/December 2020
L.) in the treatment of anxiety and depression. J Complement
Integr Med. 2016;13:195199.
40. Jam I, Sahebkar A, Eslami S, et al. The effects of crocin on the
symptoms of depression in subjects with metabolic syndrome.
Adv Clin Exp Med. 2017;26:925930.
41. Moshiri E, Basti A, Noorbala A, et al. Crocus sativus L. (petal) in
the treatment of mild-to-moderate depression: a double-blind,
randomized and placebo-controlled trial. Phytomedicine. 2006;
13:607611.
42. Kumar P, Saraswathy N,Kulkarni K. Evaluation of effect of green
tea and saffron on learning process and memory in healthy hu-
man volunteers. Pharmacol Online. 2009;2:782796.
43. Ghodrat M, Sahraei H, Razjouyan J, Meftahi G. Effects of saffron
alcoholicextract on visual short-term memory in humans: a psy-
chological study. Neurophysiol. 2014;46:247253.
44. Akhondzadeh A, Shafiee-Sabet M, Harirchian M, et al. Saffron in
the treatment of patients with mild to moderate Alzheimer's dis-
ease: a 16-week, randomized and placebo-controlled trial. JClin
Phar Therapeut. 2010;35:581588.
45. Alkhondazeh S, Sabet M, Harirchian M, et al. A 22-week, multi-
center, randomized, double-blind controlled trial of Crocus
sativus in the treatment of mild to moderate Alzheimer's disease.
Psychopharmacology (Berl). 2010;207:637643.
46. Farokhnia M, 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 random-
ized clinical trial. Hum Psychopharmacol. 2014;29:351359.
47. 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 Alzheim Dis. 2016;54:129133.
48. Azimi P, Ghuasvand R, Feizi A, et al. Effects of cinnamon, carda-
mom, saffron and ginger consumption on markers of glycemic
control, lipid profiles, oxidative stress, and inflammation in type
2 diabetes patients. Rev Diab Stud. 2014;11:258266.
49. Azimi P, Ghiasvand R, Feizi A, et al. Effect of cinnamon, cardamom,
saffron and ginger consumption on blood pressure and a marker
of endothelial function in patients with type 2 diabetes mellitus: a
randomized controlled clinical trial. Blood Press. 2016;25:133140.
50. Ebrahimi F, Aryaeian N, Pahlavani N, et al. The effect of saffron
(Crocus sativus L.) supplementation on blood pressure, and re-
nal and liver function in patients with type 2 diabetes mellitus: a
double blinded, randomized clinical trial. Avicenna J Phytomed.
2019;9:322333.
51. Ebrahimi F, Sahebkar A, Pahlavani N, et al. Effects of saffron sup-
plementation on inflammation and metabolic responses in type 2
diabetic patients: a randomized, double-blind, placebo-controlled
trial. Diab Metabol Syndr Obes Targ Ther. 2019;12:21072115.
52. Mobasseri M, Ostadrahimi A, Tajaddini A, et al. Effects ofsaffron
supplementation on glycemia and inflammation in patients
with type 2 diabetes mellitus: a randomized double-blind,
placebo-controlled clinical trial study. Diab Metabol Synd
Clin Res Rev. 2020;14:527534.
53. Aleali A, Amani R, Shahbazian H, et al. The effect of hydroalcoholic
saffron (Crocus sativus L.) extract on fasting plasma glucose, HbA
1C
,
lipid profile, liver, and renal function in patients with type 2 diabetes
mellitus: a randomized double-blind clinical trial. Phytother Res.
2019;33:16481657.
54. Karimi-Nazari E, Nadjarzadeh A, Masoumi R, et al. Effect of saffron
(Crocus sativus L.) on lipid profile, glycemic indices and antioxi-
dant status among overweight/obese prediabetic individuals: a
double-blinded, randomized controlled trial. Clin Nutr ESPEN.
2019;34:130136.
55. Shahbazian H, Aleali A, Amani R, et al. Effects of saffron on ho-
mocysteine, and antioxidant and inflammatory biomarkers
levelsin patients with type 2 diabetes mellitus: a randomized,
double-blind clinical trial. Avicenna J Phytother. 2019;9:
436445.
56. Milajerdi A, Jazayeri S, Hashemzadeh N, et al. The effect of saf-
fron (Crocus sativus L.) hydroalcoholic extract on metabolic
control in type 2 diabetes mellitus: a triple-blinded randomized
clinical trial. JResMedSci. 2018;23:16.
57. Milajerdi A, Jazayeri S, Bitarafan V, et al. The effect of saffron
(Crocus sativus L.) hydro-alcoholic extract on liver and renal
functions in type 2 diabetic patients: a double-blinded ran-
domized and placebo control trial. J Nutr Intermed Metab.
2017;9:611.
58. Sepahi S, Mohajeri S, Hosseini S, et al. Effects of crocin on dia-
betic maculopathy: a placebo-controlled randomized clinical
trial. Am J Ophthalmol. 2018;190:8998.
59. Shemshian M, Mousavi S, Norouzy A, et al. Saffron in metabolic
syndrome: its effects on antibody titers to heat-shock proteins
27, 60, 65, 70. J Complement Integr Med. 2014;11:4349.
60. Kermani T, Mousavi S, Shemshian M, et al. Saffron supplements
modulate serum pro-oxidantantioxidant balance in patients
with metabolic syndrome: a randomized, placebo-controlled
clinical trial. Avicenn J Phytomed. 2015;5:427433.
61. Kermani T, Zebarjadi M, Mehrad-Majd H, et al. Anti-inflammatory
effect of Crocus sativus on serum cytokine levels in subjects with met-
abolic syndrome: a randomized, double-blind, placebo-controlled
trial. Curr Clin Pharmacol. 2017;12:122126.
62. Zilaee M, Soukhtanloo M, Ghayour-Mobarhan M, et al. Effect of
saffron on serum leptin levels in patients with metabolic syn-
drome, a double-blind, randomized and placebo-controlled trial
study. Progr Nutr. 2018;20(suppl 1):140144.
63. Nikbakht-Jam I, Khademi M, Nosrati M, et al. Effect of crocin
from saffron on pro-oxidantantioxidant balance in subjects
with metabolic syndrome: a randomized, placebo-controlled
clinical trial. Eur J Integr Med. 2016;8:307312.
64. Javandoost A, Afshari A, Nikbakht-Jam I, et al. Effect of crocin, a
carotenoid from saffron, on plasma cholesterol ester transfer
protein and lipid profile in subjects with metabolic syndrome:
a double-blind randomized clinical trial. ARYA Atheroscler.
2017;13:245252.
65. Kermani T,Kazemi T, Molki S, et al. The efficacyof crocin of saf-
fron (Crocus sativus L.) on the components of metabolic syn-
drome: a randomized controlled clinical trial. J Res Pharm
Pract. 2017;6:228232.
66. Abedimanesh N, Bathaie S, Abedimanesh S, et al. Saffron and
crocin improved appetite, dietary intakes and body composition
in patients with coronary artery disease. J Cardiovasc Thorac
Res. 2017;9:200208.
67. Abedimanesh N, Motlagh B, Abedimanesh S, et al. Effects of
crocin and saffron aqueous extract on gene expression of SIRT1,
AMPK, LOX1, NF-kB, and MCP-1 in patients with coronary ar-
tery disease: a randomized placebo-controlled study. Phytother
Res. 2020;35:11141122. https://doi.org/10.1002/pyr.6580.
68. Abedimanesh S, Bathaie S, Ostadrahimi A, et al. The effect of
crocetin supplementation on markers of atherogenic risk in patients
with coronary artery disease: a pilot, randomized, double-blind,
placebo-controlled clinical trial. Food Funct. 2019;10:74617475.
69. Dai L, Chen L, Wang W. Safety and efficacy of saffron (Crocus
sativus L.) for treating mild to moderate depression: a systematic
review and meta-analysis. JNervMentDis. 2020;208:269276.
70. Marx W, Lane M, Rocks T, et al. Effect of saffron supplementa-
tion on symptoms of depression and anxiety: a systematic re-
view and meta-analysis. Nutr Rev. 2019;77:557571.
71. Toth B, Hegyi P, Lantos T, et al. The efficacy of saffron in the
treatment of mild to moderate depression: a meta-analysis.
Planta Med. 2019;85:2431.
72. Khaksarian M, Behzadifar M, Behzadifar M, et al. The efficacy of
Crocus sativus (saffron) versus placebo and fluoxetine in treating
Volume 55, Number 6, November/December 2020 Nutrition Today
®
301
depression: a systematic review and meta-analysis. Psychol Res
Behav Manage. 2019;12:297305.
73. Yang X, Chen X, Fu Y, et al. Comparative efficacy and safety of
Crocus sativus L. for treating mild to moderate major depressive
disorder in adults: a meta-analysis of randomized controlled tri-
als. Neuropsych Disease Treat. 2018;14:12971305.
74. Ghaderi A, Asbaghi O, Reiner O, et al. The effects of saffron
(Crocus sativus L.) on mental health parameters and C-reactive
protein: a meta-analysis of randomized clinical trials. Complement
Ther Med. 2020;48:102250. doi.org/10.1016/j.ctim.2019.102250.
75. Lopresti A, Drummond P. Saffron (Crocus sativus) for depression:
a systematic review of clinical studies and examination of underly-
ing antidepressant mechanisms of action. Hum Psychopharmacol.
2014;29:517527.
76. Ravindran A, Balneaves L, Faulkner G, et al. Canadian Network
for Mood and Anxiety Treatments (CANMAT) 2016 clinical
guidelines for the management of adults with major depressive
disorder: section 5. Complementary and alternative medicine
treatments. Can J Psychiatry. 2016;61:576587.
77. Shafiee M, Arekhi S, Omranzadeh A, Sahebkar A. Saffron in the
treatment of depression, anxiety and other mental disorders:
current evidence and potential mechanisms of action. JAffect
Dis. 2018;227:330337.
78. Avgerinos K, Vrysis C, Chaitidis N, et al. Effects of saffron
(Crocus sativus L.) on cognitive function. A systematic review
of RCTs. Neurolog Sci. 2020;41:27472754. doi.org/10.1007/
s10072-020-04427-0.
79. Dome P, Tombor L, Lazary J, Gonda X, Rihmer Z. Natural health
products, dietary minerals, and over-the-counter medications as
add-on therapies to antidepressants in the treatment of major de-
pressive disorder: a review. Brain Res Bull. 2019;148:5178.
80. Singh D. Neuropharmacological aspects of Crocus sativus L.:a
review of preclinical studies and ongoing clinical research.
CNS Neurol Disor Drug Targets. 2015;14:880902.
81. Hatziagapiou K, Kakouri E, Lambrou G, et al. Antioxidant prop-
erties of Crocus sativus L. and its constituents and relevance to
neurodegenerative diseases: focus on Alzheimer's and Parkinson's
disease. Curr Neuropharmacol. 2019;17:377402.
82. Hadipour M, Meftahi G, Afarinesh M, et al. Crocin attenuates the
granular cells damages on the dentate gyrus and pyramidal neu-
rons in the CA3 regions of the hippocampus and frontal cortex in
the rat model of Alzheimer's disease. J Chem Neuroanat. 2020;
101837. doi.org/10.1016/j.chemneu.2020.101837.
83. Batarseh Y, Bharate S, Kumar V, et al. Crocus sativus extract
tightens the blood-brain barrier, reduces amyloid ß load and
related toxicity in 5XFAD mice. ACS Chem Nerosci. 2017;8:
17561766.
84. Giannoulaki P, Kotzakioulafi E, Chourdakis M, et al. Impact of
Crocus sativus L on metabolic profile in patients with diabetes
mellitus or metabolic syndrome: a systematic review. Nutrients.
2020;12:1424.
85. Rahmani J, Bazmi E, Clark C, Nazari S. The effect of saffron sup-
plementation on waist circumference, HbA
1C
, and glucose me-
tabolism: a systematic review and meta-analysis of randomized
clinical trials. Complement Ther Med. 2020;49:102298. doi.org/
10.1016/j.ctim.2020.102298.
86. Roshanravan B, Samarghandian S, Ashrafizadeh M, et al. Meta-
bolic impact of saffron: an updated systematic and meta-analysis
of randomized clinical trials. Arch Physiol Biochem. 2020;113.
https://doi.org/10.1080/13813455.2020.1716020.
87. Asbaghi A, Soltani S, Norouzi N, et al. The effect of saffron supple-
mentation on blood glucose and lipid profile: a systematic review
and meta-analysis of randomized controlled trials. Complement
Ther Med. 2019;47:102158. doi.org/10.1016/j.ctim.2019.07.017.
88. Rahmani J, Manzari N, Thompson J, et al. The effect of saffron on
weight and lipid profile: a systematic review, meta-analysis, and
dose-response of randomized clinical trials. Phytother Res.2019;
33:22442255.
89. Pourmasoumi M, Hadi A, Najafgholizadeh A, et al. Clinical evi-
dence on the effects of saffron (Crocus sativus L.) on cardiovas-
cular risk factors: a systematic review meta-analysis. Pharmacol
Res. 2019;139:348359.
90. Yaribeygi H, Zare V, Butler A, et al. Antidiabetic potential of saf-
fron and its active constituents. Cell Physiol. 2019;34:86108617.
91. Shafiee M, Moghaddam N, Nosrati M, et al. Saffron against com-
ponents of metabolic syndrome: current status and prospective.
J Agric Food Chem. 2017;65:1083710843.
92. Razavi B, Hosseinzadeh H. Saffron: a promising natural medi-
cine in the treatment of metabolic syndrome. J Sci Food Agric.
2017;97:16791685.
93. Hatziagapiou K, Lambrou G. The protective role of Crocus
sativus L. (saffron) against ischemia-reperfusion injury, hyperlip-
idemia and atherosclerosis: nature opposing cardiovascular dis-
ease. Curr Cardiol Rev. 2018;14:272289.
94. Maleki-saghooni N,Mirzaeii K, Hosseinzadeh H, et al. A system-
atic review and meta-analysis of clinical trials on saffron (Crocus
sativus) effectiveness and safety on erectile dysfunction and se-
men parameters. Avicenna J Phytomed. 2018;8:198209.
95. Leone S, Recinella L, Chiavaroli A, et al. Phytotherapic use of the
Crocus sativus L. (saffron) and its potential applications: a brief
overview. Phytother Res. 2018;32:23642375.
96. Ranjbar H,Ashrafizaveh A. Effects of saffron (Crocus sativus)on
sexual dysfunction among men and women: a systematic re-
view and meta-analysis. Avicenna J Phytomed. 2019;9:419427.
97. Heitmar R, Brown J, Kyrou I. Saffron (Crocus sativus L.)inocular
diseases: a narrativereview of the existing evidence from clinical
studies. Nutrients. 2019;11:649663.
98. Fernandez-Albarral J, DeHoz R, Ranirez A, et al. Beneficial ef-
fects of saffron (Crocus sativus L.) in ocular pathologies, particu-
larly neurodegenerative retinal diseases. Neural Regen Res.
2020;15:14081416.
99. Agha-Hosseini M, Kashani L, Aleyaseen A, et al. Crosus sativus L.
(saffron) in the treatment of premenstrual syndrome: a double-
blind, randomized and placebo-controlled trial. BJOG. 2008;
115:515519.
100. Fukui H, Toyoshima K, Komaki R. Psychological and neuroen-
docrinological effects of odor of saffron (Crocus sativus).
Phytomedicine. 2011;18:726730.
101. Beiranvand S, Beiranvand N, Moghadam Z, et al. The effect of
Crocus sativus (saffron) on the severity of premenstrual syn-
drome. Eur J Integr Med. 2016;8:5561.
102. Maleki-Saghooni N, Karimi F, Moghadam Z, Najmabadi M. The
effectiveness and safety of Iranian herbal medicines for treat-
ment of premenstrual syndrome: a systematic review. Avicenna
JPhytomed. 2017;8:96113.
103. Umigai N, Takeda R, Mori A. Effect of crocetin on quality of
sleep: a randomized, double-blind, placebo-controlled, cross-
over study. Complement Ther Med. 2018;41:4751.
104. Kuratsune H, Umigai N, Takeno R, et al. Effect of crocetin from
Gardenia jasminoides Ellis on sleep: a pilot study. Phytomedicine.
2010;17:840843.
105. Lopresti A, Smith S, Metse A, Drummond P. Effects of saffron on
sleep quality in healthy adults with self-reported poor sleep: a
randomized, double-blind, placebo-controlled trial. J Clin Sleep
Med. 2020;16:937947. doi.org/10.5664/jcsm.8376.
106. Ghiasian M, Khamisabad F, Kheiripour N, et al. Effects of crocin
in reducing DNA damage, inflammation, and oxidative stress in
multiple sclerosis patients: a double-blind, randomized, and
placebo-controlled trial. J Biochem Mol Toxicol. 2019;33:e22410.
doi.org/10.1002/jbt22410.
107. Sakha F, Saeen A, Moazzeni S, et al. A randomized, triple-blind,
placebo-controlled trial to determine the effect of saffron on the
302 Nutrition Today
®
Volume 55, Number 6, November/December 2020
serum levels of MMP-9 and TIMP-1 in patients with multiple scle-
rosis. Iran J Allergy Asthma Immunol. 2020;19:297304.
108. Ashtiani A, Amirhossein L, Jadidi A, et al. The effect of novel sim-
ple saffron syrup on fatigue reduction in patients with multiple
sclerosis. J Basic Clin Physiol Pharmacol. 2020. doi.org/10.1515/
JBCPP-2020-0063.
109. Feo F, Martinez J, Martinez A, et al. Occupational allergy in saf-
fron workers. Allergy. 1997;52:633641.
110. Hassan I, Kamili A, Rasool F, et al. Contact dermatitis in saffron
workers: clinical profile and identification of contact sensitizers
in a saffron-cultivating area of Kashmir Valley of North India.
Dermatitis. 2015;26(26):136141.
111. Moneret-Vautrin D, Morisset M, Lemerdy Ph, Croizier A, Kanny G. Al-
lergy and IGE sensitization caused by spices: CICBAA data (based on
598 cases of food allergy). Allergie Immunologie. 2002;34:135140.
112. Hosseini SA, Zilaee M, Shoushtari MH, Ghasemi Dehcheshmeh
M. An evaluation of the effect of saffron supplementation on
the antibody titer to heat-shock protein (HSP) 70, hsCRP and spi-
rometry test in patients with mild and moderate persistent
allergic asthma: a triple-blind, randomized placebo-controlled
trial. Respir Med. 2018;145:2834.
113. Hosseini S, Jamshidnezhad A, Zilaee M, et al. Neural network-based
clinical prediction system for identifying the clinical effects of saffron
(Crocus sativus L.) supplement therapy on allergic asthma: model
evaluation study. JMIR Med Inform. 2020;8:e17580.
114. Mansoori P, Akhondzadeh S, Raisi F, et al. A randomized,
double-blind, placebo-controlled study of safety of the adjunc-
tive saffron on sexual dysfunction induced by a selective seroto-
nin reuptake inhibitor. JMedPlants. 2011;10:121129.
115. Modaghegh M, Shahabian M, Esmaeih H, et al. Safety evaluation
of saffron (Crocus sativus) tablets in healthy volunteers. Phytomedicine.
2009;15:10321037.
116. Mohamadpour A, Ayati Z, Parizadeh M, et al. Safety evaluation
of crocin (a constituent of saffron) tablets in healthy volunteers.
Iran J Basic Med Sci. 2013;16:3946.
117. WHO. WHO monographs on selected medicinal plants. 2007:3.
https://apps.who.int/iris/bitstream/handle/10665/42052/
9789241547024_eng.pdf.
Volume 55, Number 6, November/December 2020 Nutrition Today
®
303
... The bioactive compounds in saffron have been known effective for the treatment of certain cancers, cardiovascular and cerebrovascular illnesses, dysentery, measles, asthma, urological infections, cough, and stomach disturbances. Additionally, it possesses tranquilizing, anti-tumoral, anti-ischemic, anti-anxiolytic, anti-inflammatory, neuroprotective, DNA-protective, and especially antioxidative attributes [10][11][12][13][14][15]. For this reason, contrary to its high price, the use of saffron has increased in recent years, owing to the growing consumers' demand for food products containing nanoliposomal encapsulated SE and the effect of saffron bioactive compounds on various properties of this type of cheese. ...
Article
Full-text available
In this study, the encapsulation of saffron extract (SE) was examined at four various concentrations of soy lecithin (0.5%–4% w/v) and constant concentration of SE (0.25% w/v). Particle size and zeta potential of liposomes were in the range of 155.9–208.1 nm and −34.6–43.4 mV, respectively. Encapsulation efficiency was in the range of 50.73%–67.02%, with the stability of nanoliposomes in all treatments being >90%. Encapsulated SE (2% lecithin) was added to ricotta cheese at different concentrations (0%, 0.125%, 1%, and 2% w/v), and physicochemical and textural properties of the cheese were examined. Lecithin concentration significantly (p ≤ 0.05) affected the particle size, zeta potential, stability, and encapsulation efficiency of the manufactured liposomes. In terms of chemical composition and color of the functional cheese, the highest difference was observed between the control cheese and the cheese enriched with 2% liposomal encapsulated SE. Hardness and chewiness increased significantly (p ≤ 0.05) in the cheeses containing encapsulated SE compared to the control cheese. However, there was no significant difference in the case of adhesiveness, cohesiveness, and gumminess among different cheeses. Overall, based on the findings of this research, liposomal encapsulation was an efficient method for the delivery of SE in ricotta cheese as a novel functional food.
... Garlic, ginger, curcumin, cinnamon, or saffron are a few of the most popular CAMs used in rheumatic diseases (RDs) [5][6][7]. Saffron, in particular, is the dried stigma of the flowers of Crocus sativus L. (family Iridaceae), cultivated mainly in Southern Europe, India and Iran, and is considered as one of the most expensive culinary spices globally [8]. The medicinal properties of saffron and its constituents (safranal, crocin, and crocetin) include anti-inflammatory, antioxidant, analgesic, antihypertensive, hypolipidemic, antitussive, anticonvulsant, antidepressant, anxiolytic, anticancer, and antinociceptive characteristics [9][10][11][12][13][14][15]. ...
Article
Full-text available
Rheumatic diseases (RDs) are often complicated by chronic symptoms and frequent side-effects associated with their treatment. Saffron, a spice derived from the Crocus sativus L. flower, is a popular complementary and alternative medicine among patients with RDs. The present systematic review aimed to summarize the available evidence regarding the efficacy of supplementation with saffron on disease outcomes and comorbidities in patients with RD diagnoses. PubMed, CENTRAL, clinicaltrials.gov and the grey literature were searched until October 2021, and relevant randomized controlled trials (RCTs) were screened for eligibility using Rayyan. Risk of bias was assessed using the Cochrane’s Risk of Bias-2.0 (RoB) tool. A synthesis without meta-analysis (SWiM) was performed by vote counting and an effect direction plot was created. Out of 125 reports, seven fulfilled the eligibility criteria belonging to five RCTs and were included in the SWiM. The RCTs involved patients with rheumatoid arthritis, osteoarthritis and fibromyalgia, and evaluated outcomes related to pain, disease activity, depression, immune response, inflammation, oxidative stress, health, fatigue and functional ability. The majority of trials demonstrated some concerns regarding overall bias. Moreover, the majority of trialists failed to adhere to the formula elaborations suggested by the CONSORT statement for RCTs incorporating herbal medicine interventions. Standardization of herbal medicine confirms its identity, purity and quality; however, most trials failed to adhere to these guidelines. Due to the great heterogeneity and the lack of important information regarding the standardization and content of herbal interventions, it appears that the evidence is not enough to secure a direction of effect for any of the examined outcomes.
... Identification agents and famous medications such as second-generation antipsychotics, levothyroxine, and other drugs are substantial ways for increasing the capability of the currently available antidepressants (ADs) as nutraceuticals and over the counter (OTC) drugs in modern psychopharmacology [9]. To clarify this point, Bioactive Compounds in Health and Disease 2021; 4(5): 90-92 in many clinical trials, the therapeutic effect of saffron, with its essential components was equal to antidepressants, (fluoxetine, imipramine, and citalopram) [10][11][12]. Moreover, information from other interventional studies indicated that saffron is even more impressive compared to placebo and synthetic antidepressant drugs, especially when accompanied by antioxidants, anti-inflammatory, and serotonergic compounds etc. ...
Article
Full-text available
Throughout the centuries, people have used the dried stigma of Crocus sativus that is known as "saffron" for medicinal and nutritional purposes [1]. Studies have shown that not only is saffron well worth the money, but also, its bioactive compounds (including crocin, precrocin, and safranal that are responsible for color, taste and fragrance respectively) play a crucial role in the central nervous system to positively affect conditions such as anxiety and depression [2-5]. Saffron compounds are also neuroprotective and anxiolytic and can benefit learning and memory impairments [6].
Chapter
Crocus sativus L., an autumnal herbaceous flowering plant, is known for being the most valuable spice in the world. Because of its three main biological active compounds crocin, picrocrocin and safranal, it is highly beneficial to human health. The global demand for the spice is increasing due to its major role in the medicinal, cosmetics, perfumery and textile dye-producing industries. The thorough study of the geophyte is the need of the hour, as its production is declining year after year. The chapter discusses the origin, history, dissemination, production, economic value, physio-morphological traits, cytogenetics, penological stages, climatic adaption, agronomical practices, phytochemistry and adulteration of saffron. Additionally, an overview of the current knowledge of the biotechnological interventions and saffron’omics’ is mentioned.KeywordsCrocus sativus L.GeophyteStigmaSaffron biologySynthetic biologySaffron’omics’
Chapter
Saffron, the dried stigma of Crocus sativus L. (Iridaceae), is traditionally used as spice in several foods around the world to provide color, flavor, and aroma. Saffron is characterized by the bright yellow color of crocetin and crocins, a bitter taste that is related to picrocrocin and a delicate aroma caused mainly by the presence of safranal. The mechanism of action of major saffron metabolites and their bioavailability has not yet been resolved, although they possess excellent bioactivity. The rest of the flowers contain style, tepals, and stamens consisting of other compounds such as kaempferol and delphinidin, which have important antioxidant properties and can be used in foods, herbal remedies, and cosmetics. Recently, interest has increased in investigation of known saffron bioactivity, which is linked to the key components present in the spice. The chapter reviews and updates research on saffron properties and its main constituents as well as analytical methods for identification and quantification of components, focusing on bioactivity and bioavailability, antioxidant and therapeutic properties, and its potential applications as a functional food or nutraceutical.
Chapter
Oleoresin is a mixture of volatile and nonvolatile components available in whole extract of natural herb or spice. It principally comprises essential oils and resin. Lemongrass oleoresins come from the Cymbopogon species, which grow in the tropical and subtropical regions of the world. Oleoresin of lemongrass is a dark green-colored viscous liquid having a characteristic lemon aroma and flavor and is mostly used as a flavoring ingredient. The lemon prefix in the lemongrass specifies the characteristic lemon-like odor, which is due to the availability of citral content (mixture of two isomeric aldehydes, geranial and neral). It has been utilized in synthesizing flavors, perfumes, cosmetics, detergents, and in the food and pharmaceutical industries. Different methods are used to extract the lemongrass essential oil, but steam distillation is the most suitable method as it doesn’t alter the quality of the obtained oil. The chemical composition of lemongrass oil varies depending on its extraction methods, genetic differences, harvest period, photoperiod, plant age, farming practices, and geographical origin. Lemongrass essential oil has shown several biological activities, including antimicrobial, antifungal, antiprotozoan, antioxidant, antidiarrheal, antimutagenic, antiinflammatory, antimalarial, antinociceptive, antihepatotoxic activities, etc. Lemongrass oil is a potent food preservative because of its extraordinary antifungal and antibacterial activities.
Article
Full-text available
Neural Network-Based Clinical Prediction System for Identifying the Clinical Effects of Saffron (Crocus sativus L) Supplement Therapy on Allergic Asthma: Model Evaluation Study
Article
Full-text available
Objectives Multiple sclerosis (MS) is a progressive and often debilitating neurological disorder. This chronic disease has a high prevalence in the world and also in Iran. Fatigue is a common symptom of the disease, which causes serious mental and psychological discomfort. Simple saffron syrup, contains some compounds that can be effective in relieving the symptom. The object of this study is to investigate the effect of simple saffron syrup on fatigue in patients with MS. Methods This study is a pre-post study which evaluates the fatigue rate of MS patients (30 participants) according to the FSS scale. The participants were given a saffron simple syrup to consume a tablespoon (7.5 cc) every 8 h for two months. After 60 days of prescribing, patients are assessed for fatigue based on fatigue severity scale (FSS) criteria. Results One-way ANOVA showed that there was a notable difference between the mean score of fatigue in MS patients before and after the intervention (p<0.001). So, the fatigue severity of the subjects after saffron syrup consumption dropped dramatically for two months. (p<00.01). Conclusions According to the outcomes of this study, simple saffron syrup can be effective as an adjunct therapy for fatigue reduction in patients with MS due to effectiveness besides no significant side effects.
Article
Full-text available
Matrix metalloproteinases (MMP)-9 facilitates the migration of T-cells to central nervous system (CNS), while tissue inhibitor of metalloproteinases-1(TIMP-1) inhibits the function of MMP-9. This study aimed to determine the appropriate treatment option for multiple sclerosis (MS). Forty-three relapsing-remitting MS (RRMS) patients were randomly divided into two groups of 22 (group A, placebo) and 21 (group B, Saffron pill) individuals. Serum samples were collected from patients’ blood before using the Saffron pills/placebo pills and then after 12 months. The serum level of MMP-9 and its inhibitor, as well as TIMP-1, were measured by ELISA kits. MMP-9 serum levels noticeably decreased in patients with MS following 12 months of treatment with Saffron pills (p=0.006) while the changes were not significant before and after 12 months of treatment with placebo pills. Although the levels of TIMP-1 increased significantly after one year treating with Saffron pills (p=0.0002), a considerable difference was not observed before and after taking the placebo pills. The study finding revealed that 12-months treatment with Saffron could have a significant role in reducing the serum level of MMP-9 and increasing the serum level of TIMP-1 in RRMS patients. Therefore, modulating the serum levels of MMP-9 as an important regulator of T cell trafficking to the CNS might be a promising strategy in the treatment of MS patients.
Article
Full-text available
Background: Experimental studies demonstrated a positive effect of administration of Crocus sativus L. (saffron) and its bioactive ingredients on metabolic profile through their antioxidant capacity. Purpose: To determine if the use of saffron in humans is beneficial to patients with diabetes mellitus (DM) or metabolic syndrome (MS). Methods: This systematic review includes 14randomized control trials that investigated the impact of saffron administration and its bioactive ingredient crocin on the metabolic profile of patients with DM, MS, prediabetes, and coronary artery disease. We documented the following clinical outcomes: fasting blood glucose (FBG), glycated haemoglobin (HbA1c), total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, systolic, and diastolic blood pressure. Results: Eight studies examined the efficacy of saffron in patients with DM, four with the metabolic syndrome, one with prediabetes and one with coronary artery disease. A favorable effect on FBG was observed. The results regarding blood lipids and blood pressure were inconclusive in the current review. Conclusions: According to the available limited evidence, saffron may have a favorable effect on FBG. Many of the studies in the reviewed literature are of poor quality, and more research is needed in this direction to confirm and establish the above findings.
Article
Full-text available
Background New evidence indicates that overproduction of pro-inflammatory cytokines is responsible for the development of diabetes difficulties. Some herbals such as saffron, may control inflammation and improve the hyperglycemic states in diabetic patients. Therefore, this investigation aimed to assess the effects of saffron supplementation on fasting glucose and inflammatory markers levels in patients with type2 diabetes mellitus (T2DM). Methods In this randomized double-blind, placebo-controlled clinical trial, 60 T2DM patients were randomly assigned into two groups as saffron and placebo (n = 30) receiving 100 mg/day saffron powder or starch capsules (1 capsule) for a duration of 8 weeks. Fasting blood sample was collected at baseline and at the end of the intervention. Fasting blood glucose (FBG) was immediately analyzed by the auto-analyzer. The serum level of Interleukin −6 (IL-6), Tumor necrosis factor-alpha (TNF-α), and Interleukin-10 (IL-10) were measured using ELISA assay by laboratory kits. Also, Real-time quantitative reverse transcription (RT-PCR) assay measured the expression level of TNF-α, IL-6, and IL-10 at the mRNA level. Results Saffron supplementation significantly decreased the FBG levels within 8 weeks compared to placebo (130.93 ± 21.21 vs 135.13 ± 23.03 mg/dl, P = 0.012). Moreover, the serum level of TNF-α notably reduced in the saffron group compared to the placebo group (114.40 ± 24.28 vs 140.90 ± 25.49 pg/ml, P < 0.001). Also, saffron supplementation significantly down-regulated the expressions of TNF-α (P = 0.035) and IL-6 mRNA levels (P = 0.014). Conclusion In our study, it was indicated that saffron modulates glucose levels as well as inflammation status in T2DM patients through decreasing the expressions levels of some inflammatory mediators. Also, further investigations are necessary to confirm the positive effects of saffron as a complementary therapy for T2DM patients.
Article
Full-text available
Saffron (Crocus sativus L.) has been traditionally used in food preparation and as a medicinal plant. It currently has numerous therapeutic properties attributed to it, such as protection against ischemia, as well as anticonvulsant, antidepressant, anxiolytic, hypolipidemic, anti-atherogenic, anti-hypertensive, antidiabetic, and anti-cancer properties. In addition, saffron has remarkable beneficial properties, such as anti-apoptotic, anti-inflammatory and antioxidant activities, due to its main metabolites, among which crocin and crocetin stand out. Furthermore, increasing evidence underwrites the possible neuroprotective role of the main bioactive saffron constituents in neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases, both in experimental models and in clinical studies in patients. Currently, saffron supplementation is being tested for ocular neurodegenerative pathologies, such as diabetic retinopathy, retinitis pigmentosa, age-related macular degeneration and glaucoma, among others, and shows beneficial effects. The present article provides a comprehensive and up to date report of the investigations on the beneficial effects of saffron extracts on the main neurodegenerative ocular pathologies and other ocular diseases. This review showed that saffron extracts could be considered promising therapeutic agents to help in the treatment of ocular neurodegenerative diseases.
Article
Background: Metabolic syndrome is a risk factor for cardiovascular disease and diabetes mellitus. A decreased level of serum leptin is reported for obese populations. Beneficial effects of saffron on human health, including appetite-regulation, have been reported previously. The aim of this study was to investigating the effect of saffron supplementation on serum leptin levels in patients with metabolic syndrome. Material and method: Patients with metabolic syndrome were randomly divided into two groups; a case group, receiving saffron and a control group, receiving placebo. Concentration of serum leptin was measured at baseline and after 12 weeks of the start of study. SPSS software was used to analyze the data. Results: There was a borderline (p=0.05) significant difference in serum leptin before and after treatment with saffron, but not in the placebo group. There was a significant difference in serum leptin concentrations between the groups (p=0.001). Conclusion: Saffron supplementation has no significant effect on serum leptin levels in patients with metabolic syndrome.
Article
Amyloid β-peptides (Aβ) are considered as a major hallmark of Alzheimer's disease (AD) that can induce synaptic loss and apoptosis in brain regions, particularly in the cortex and the hippocampus. Evidence suggests that crocin, as the major component of saffron, can exhibit neuromodulatory effects in AD. However, specific data related to their efficacy to attenuate the synaptic loss and neuronal death in animal models of AD are limited. Hence, we investigated the efficacy of crocin in the CA3 and dentate gyrus (DG) regions of the hippocampus and also in frontal cortex neurons employing a rat model of AD. Male Wistar rats were randomly divided into control, sham, AD model, crocin, and AD model + crocin groups, with 8 rats per group. AD model was established by injecting Aβ1–42 into the frontal cortex rats, and thereafter the rats were administrated by crocin (30 mg/kg) for a duration of 12-day. The number of live cells, neuronal arborization and apoptosis were measured using a Cresyl violet, Golgi-Cox and TUNEL staining, respectively. Results showed that, the number of live cells in the hippocampus pyramidal neurons in the CA3 and granular cells in the DG regions of the AD rats significantly decreased, which was significantly rescued by crocin. Compared with the control group, the axonal, spine and dendrites arborization in the frontal cortex and CA3 region of the AD model group significantly decreased. The crocin could significantly reverse this arborization loss in the AD rats (P < 0.05). The apoptotic cell number in the CA3 and DG regions in the AD model group was significantly higher than that of the control group (P < 0.05), while crocin significantly decreased the apoptotic cell number in the AD group (P < 0.05). Conclusion. Crocin can improve the synaptic loss and neuronal death of the AD rats possibly by reducing the neuronal apoptosis.
Article
IntroductionImprovement of cognitive function may be desirable for healthy individuals and clinically beneficial for those with cognitive impairment such as from Alzheimer’s disease (AD) or mild cognitive impairment (MCI). The aim of this systematic review is to investigate the cognitive effects of oral saffron intake, in patients with MCI/AD and/or in non-demented individuals, by following the PRISMA guidelines.Methods We performed a literature search on MedLine, Cochrane library, and ClinicalTrials.gov to identify randomized controlled trials (RCTs) investigating the effects of oral saffron administration in patients with MCI/AD and/or in non-demented individuals.ResultsFive studies (enrolling 325 individuals) met our inclusion criteria. Four studies included patients with MCI/AD, and one study included cognitively normal individuals. Saffron was well-tolerated in all groups. Regarding cognitively impaired patients, scores on Alzheimer’s Disease Assessment Scale-cognitive subscale or Mini mental state examination were significantly better when saffron was compared with placebo and did not differ significantly when saffron was compared with donepezil or memantine. Saffron effects on functional status were similar with its effects on cognition.Conclusions Saffron was shown to be equally effective to common symptomatic drugs for MCI/AD and resulted in no difference in the incidence of side effects, when compared with placebo or drugs. The promising results should be seen cautiously, since the evidence was derived from studies with potentially high risk of bias (ROB). RCTs with larger sample sizes and low ROB are required to definitively assess the potential role of saffron as an MCI/AD treatment.
Article
STUDY OBJECTIVES: Herbal medicines are frequently used by adults with sleep difficulties. However, evidence of their efficacy is limited. Therefore, the goal of this study was to examine the sleep-enhancing effects of a standardised saffron extract (affron). METHODS: This was a 28-day, parallel-group, double-blind, randomised controlled trial. Sixty-three healthy adults aged 18 to 70 with self-reported sleep problems were recruited and randomised to receive either saffron extract (affron, 14mg twice daily) or a placebo. Outcome measures included the Insomnia Severity Index (ISI) (primary outcome measure) collected at baseline, days 7, 14, 21, and 28; Restorative Sleep Questionnaire (RSQ) and Pittsburgh Sleep Diary (PSD) collected on days -1, 0, 3, 7, 14, 27, and 28. RESULTS: Based on data collected from 55 participants, saffron was associated with greater improvements in ISI total score (p=.017), RSQ total score (p=.029), and PSD sleep quality ratings (p=.014) than the placebo. Saffron intake was well-tolerated with no reported adverse effects. CONCLUSIONS: Saffron intake was associated with improvements in sleep quality in adults with self-reported sleep complaints. Further studies using larger samples sizes, treatment periods, objective outcome measures, and volunteers with varying demographic and psychographic characteristics are required to replicate and extend these findings.