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ORIGINAL ARTICLE: Saffron in the treatment of patients with mild to moderate Alzheimer’s disease: a 16-week, randomized and placebo-controlled trial

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  • iranian Center for Neurological Research-Neuroscience institute-Tehran University of Medical Sciences

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WHAT IS KNOWN: Herbal medicines have been used in the treatment of behavioural and psychological symptoms of dementia but with variable response. Crocus sativus (saffron) may inhibit the aggregation and deposition of amyloid β in the human brain and may therefore be useful in Alzheimer's disease (AD). The goal of this study was to assess the efficacy of saffron in the treatment of mild to moderate AD. Forty-six patients with probable AD were screened for a 16-week, double-blind study of parallel groups of patients with mild to moderate AD. The psychometric measures, which included AD assessment scale-cognitive subscale (ADAS-cog), and clinical dementia rating scale-sums of boxes, were performed to monitor the global cognitive and clinical profiles of the patients. Patients were randomly assigned to receive capsule saffron 30 mg/day (15 mg twice per day) (Group A) or capsule placebo (two capsules per day) for a 16-week study. After 16 weeks, saffron produced a significantly better outcome on cognitive function than placebo (ADAS-cog: F=4·12, d.f.=1, P=0·04; CDR: F=4·12, d.f.=1, P=0·04). There were no significant differences in the two groups in terms of observed adverse events. This double-blind, placebo-controlled study suggests that at least in the short-term, saffron is both safe and effective in mild to moderate AD. Larger confirmatory randomized controlled trials are called for.
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ORIGINAL ARTICLE
Saffron in the treatment of patients with mild
to moderate Alzheimer’s disease: a 16-week,
randomized and placebo-controlled trial
S. Akhondzadeh*PhD,M.Shafiee-SabetMD,M.H.HarirchianMD,M.ToghaMD,
H. CheraghmakaniMD,S.RazeghiMSc, S. Sh. Hejazi§ MD,M.H.Yousefi§MD,
R. AlimardaniMD,A.JamshidiPhD,F.Zare*MD and A. Moradi* MD
*Psychiatric Research Center, Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Institute
of Medicinal Plants (ACECR), Tehran, Department of Neurology, Tehran University of Medical Sciences,
Tehran, §Department of Neurology, Qom University of Medical Sciences, Qom and Office for Herbal
Drugs, Ministry of Health and Medical Education, Tehran, Iran
ABSTRACT
What is known: Herbal medicines have been used
in the treatment of behavioural and psychological
symptoms of dementia but with variable
response. Crocus sativus (saffron) may inhibit the
aggregation and deposition of amyloid bin the
human brain and may therefore be useful in
Alzheimer’s disease (AD).
Objective: The goal of this study was to assess the
efficacy of saffron in the treatment of mild to
moderate AD.
Methods: Forty-six patients with probable AD
were screened for a 16-week, double-blind study
of parallel groups of patients with mild to
moderate AD. The psychometric measures,
which included AD assessment scale-cognitive
subscale (ADAS-cog), and clinical dementia
rating scale-sums of boxes, were performed to
monitor the global cognitive and clinical
profiles of the patients. Patients were randomly
assigned to receive capsule saffron 30 mg day
(15 mg twice per day) (Group A) or capsule
placebo (two capsules per day) for a 16-week
study.
Results: After 16 weeks, saffron produced a sig-
nificantly better outcome on cognitive function
than placebo (ADAS-cog: F=4Æ12, d.f. = 1,
P=0Æ04; CDR: F=4Æ12, d.f. = 1, P=0Æ04). There
were no significant differences in the two groups
in terms of observed adverse events.
What is new and conclusion: This double-blind,
placebo-controlled study suggests that at least in
the short-term, saffron is both safe and effective
in mild to moderate AD. Larger confirmatory
randomized controlled trials are called for.
Keywords: Alzheimer’s disease, clinical trial,
saffron
INTRODUCTION
Alzheimer’s disease (AD) is the most common
cause of dementia in the elderly (1). The onset of
the disease is insidious, generally occurring after
the age of 55 years and increasing in incidence with
advancing age. The average risk of developing AD
is approximately 5%at age 65 years and subse-
quently increasing 2-fold every 5 years. The clinical
course is marked by a gradual deterioration of
intellectual function, a decline in the ability to
accomplish routine activities of daily living, and
enduring changes in personality and behaviour (1,
2). One of the hallmarks of pathology of AD is the
presence of numerous amyloid plaques in the
cerebral cortex (3). The major component of amy-
loid plaques is amyloid b, which is derived from
the amyloid precursor protein (APP). APP is pres-
Received 29 July 2009, Accepted 9 September 2009
Correspondence: Shahin Akhondzadeh, PhD, Psychiatric
Research Center, Roozbeh Psychiatric Hospital, Tehran Univer-
sity of Medical Sciences, South Kargar Street, Tehran 13337, Iran.
Tel.: +98 21 88281866; fax: + 98 21 55419113; e-mail: s.akhond@
neda.net
Journal of Clinical Pharmacy and Therapeutics (2010) doi:10.1111/j.1365-2710.2009.01133.x
2010 The Authors. Journal compilation 2010 Blackwell Publishing Ltd 1
ent in the brain and peripheral tissues (4, 5). The
treatments of choice in AD are cholinesterase
inhibitors and NMDA-receptor antagonists,
although doubts remain about the therapeutic
effectiveness of these drugs (6). Herbal medicines
are being used by about 80%of the world popu-
lation primarily in the developing countries for
primary health care (7, 8). The growth in the pop-
ularity of alternative approaches to health care has
led to an interest in the treatment of dementia
through herbal remedies which may be cognition-
enhancing (6). Indeed, herbal medicines have been
used in the treatment of behavioural and psycho-
logical symptoms of dementia but with variable
response (9). Some plant species, which have been
used in traditional medicine, for this effect, have a
historically demonstrable lack of toxicity (6). There
is now an increase in studies investigating the
action of the extracts of some of these plants. Of
particular interest are those which are thought to
have an action similar to the approved drugs, or an
action which may be linked to what is known or
believed about AD and vascular dementia (6).
Ginkgo biloba is an herbal medicine that has been
used to treat a variety of ailments for thousands of
years in China. An extract of G. biloba has been
found in several studies to improve the symptoms
and slow the progression of AD (10). It has been
reported that Melissa officinalis (lemon balm) and
Salvia officinalis (sage) improve cognitive function
and reduces agitation in patients with mild to
moderate AD (11, 12). Crocus sativus L., commonly
known as saffron, is used in folk medicine as an
antispasmodic, eupeptic, gingival sedative, antica-
tarrhal, nerve sedative, carminative, diaphoteric,
expectorant, stimulant, stomachic and aphrodisiac
(6, 13). Furthermore, it has been reported that
saffron extract or its active constituents have
anticonvulsant, antidepressant, anti-inflammatory,
and antitumour effects, and acts as a radical
scavenger and improves learning and memory as
well as promote the diffusivity of oxygen in
different tissues (6, 13). Saffron extract also has
chemopreventive and showed protective effects on
genotoxin-induced oxidative stress in Swiss albino
mice (13). Recently, a number of clinical trials
have shown that this herb is as effective as
fluoxetine and imipramine in the treatment of mild
to moderate depression (14–16). Three main
chemical compounds have been identified in
saffron: carotinoids which give it the bright red
colouring; picrocrocin, which gives the spice its
characteristic bitter taste and safranal, which pro-
vides the spicy aroma. The carotenoid pigments
consist of crocetin di-(b-DD-glucose)-ester, crocetin-
(b-DD-gentiobiosyl)-(b-DD-glucosyl)-ester and croce-
tin-di-(b-DD-digentiobiosyl)-ester(crocin). Crocin is
the actual active component involved in both the
improvement of learning and memory and pre-
ventive effect of long-term potentiation (LTP)
blocked by ethanol in vivo (13). It has been also
reported that crocin selectively antagonizes the
inhibitory effect of ethanol on NMDA receptor-
mediated responses in hippocampal neurons (17).
This action of crocin may underlie the antagonism
against ethanol-induced memory impairment (18).
Thus, crocin can be used as a new pharmacological
tool for studying the mechanism of ethanol inhi-
bition of NMDA receptor activities (17). Therefore,
it can be concluded that crocin may have potential
for treating neurodegenerative damage induced by
oxidative stress (19, 20). A recent study also
showed that C. sativus has antioxidant and anti-
amyloidogenic activity, thus reinforcing ethno-
pharmacological observations that C. sativus had a
positive effect on cognitive function (21). This
study suggested that C. sativus might inhibit the
aggregation and deposition of amyloid bin the
human brain (21).
Iran as the world’s largest producer of saffron
has considerable knowledge in the use of this
traditional herbal medicine. But, unfortunately,
Iran has not been able to capitalize on this wealth of
information and promote the use of saffron in the
developed world despite the world-wide renewed
interest in herbal medicines (6). This may be due to
inadequate evidence despite the increasing
evidence from Persian traditional medicine as well
as recent basic research that saffron may be useful
for treating AD (18, 21–24). Our objective was to
assess the efficacy of C. sativus in the treatment of
mild to moderate AD, using a double-blind,
randomized, placebo-controlled trial design.
METHODS
Setting
This trial was a 16-week, double-blind study of
parallel groups of patients with mild to moderate
2010 The Authors. Journal compilation 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics
2S. Akhondzadeh et al.
AD and was undertaken at three sites in Iran from
January 2006 to January 2009.
Participants
Forty-six patients with probable AD of mild to
moderate severity were screened for study entry.
Diagnosis of AD was established according to the
criteria of Diagnostic and Statistical Manual of
Mental Disorders, 4th edition (25). The subjects
were classified with probable AD status according
to the criteria of the National Institute of
Neurologic and Communicative Disorders and
Stroke-Alzheimer’s Disease and Related Disorders
Association (26). Patients had to provide computed
tomography or magnetic resonance imaging scans,
performed within one year before or at the
screening, for this study to demonstrate absence of
clinically significant multi-infarct dementia or
active cerebrovascular disease. The inclusion cri-
teria were age older than 55 years and baseline
mini-mental state examination (MMSE) score of
15–26 (inclusive) (27). Patients with AD who may
also have cerebrovascular disease as evidenced by
risk factors such as hypertension, elevated choles-
terol levels, diabetes and smoking, but in stable
condition, were also eligible to enter into the study.
The patients also had to have a knowledgeable and
reliable caregiver to accompany the participant to
all trial visits and supervise administration of the
trial medication as one of the inclusion criteria.
Patients were excluded if they had evidence of
cardiovascular disease that was likely to interfere
with study participation and completion, or if they
had any other neurodegenerative disorders. Addi-
tional exclusion criteria included any clinically
significant psychiatric, hepatic, renal, pulmonary,
metabolic or endocrine conditions; urinary outflow
obstruction or active peptic ulcer or a history of
epilepsy or significant drug or alcohol abuse.
Patients were also excluded from the study if they
had received cholinomimetic therapy for AD
within the preceding 60 days and earlier discon-
tinuation was not solely for the purpose of study
enrollment. Any other antidementia medication
(e.g., chronic non-steroidal anti-inflammatory
drugs, selegiline or estrogen) also had to be
discontinued before study entry. Drugs with a
psychotropic action were discontinued 48 h before
cognitive evaluation. The protocol was approved
by the Institutional Review Board (IRB) of Tehran
University of Medical Sciences (Grant No. 4843).
The patients and their legally authorized repre-
sentative provided informed consent in accordance
with the procedures outlined by the local IRB, and
were informed that they could withdraw from trial
at any time. The trial was performed in accordance
with the Declaration of Helsinki and subsequent
revisions (28).
Measurements
The psychometric measures, which included the
MMSE, AD Assessment Scale-cognitive subscale
(ADAS-cog) (29), and clinical dementia rating
scale–sums of boxes (CDR-SB) (30), were performed
to monitor the global cognitive and clinical profiles
of the subjects. All measures were administered at
baseline and every 2 weeks after the treatment
started.
Intervention
Patients were randomized to receive capsule of
saffron or capsule of placebo in a 1 : 1 ratio using a
computer-generated code to receive a twice-daily
capsule of saffron or a capsule of placebo. No
individual participant randomization code was
revealed during the trial. Treatment codes were
unblinded at the termination of the study after the
database was locked. Placebo and saffron capsules
were visually identical. In this double-blind,
multicenter trial, patients were randomly assigned
to receive capsule saffron 30 mg day (15 mg twice
per day) (Group A) or capsule of placebo (two
capsules per day) for a 16-week study.
Preparation of capsule of saffron
The saffron used in this study was donated by
Green Plants of Life Co (IMPIRAN, Tehran, Iran)
and was identified by the Department of Cultiva-
tion and Development of Institute of Medicinal
Plants, Tehran, Iran. The extract of stigmas was
prepared as follows: 120 gof dried and milled
stigmas was extracted with 1800 mL ethanol (80%)
by percolation procedure in three steps and then
the ethanol extract was dried by evaporation at a
temperature of 35–40 C. Each capsule contained
dried extract of saffron (15 mg), lactose (filler),
2010 The Authors. Journal compilation 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics
Saffron in the treatment of Alzheimer’s disease 3
magnesium stearate (lubricant) and sodium starch
glycolate (disintegrant). The extract was standard-
ized by safranal and crocin. The likely most ther-
apeutically important compounds in saffron are
crocin, picocrocin and safranal. The amounts of
these main compounds can be used to express the
quality of saffron. The extract was standardized by
safranal and crocin contents. Drug samples are
evaluated by a safranal and crocin value by means
of a spectrophotometric method. Safranal and
crocin value are expressed as direct reading of the
absorbance at about 330 nm and 440 nm,
respectively. Each capsule had 0Æ13–0Æ15 mg
safranal and 1Æ65–1Æ75 mg crocin.
Safety evaluation
All adverse events, reported or observed, were
recorded at each visit. Routine physical examina-
tions were conducted at each visit. Complete physi-
cal examinations, including 12 lead ECG recordings,
were conducted at week 0, week 8, and week 16.
Statistical analysis
The primary efficacy analysis was done with data
from the intention-to-treat population with the last
observation carried forward procedure, defined as
all patients randomly assigned to treatment who
received at least one dose of study drug. A two-way
repeated measures analysis of variance (time–treat-
ment interaction) was used. We considered the two
groups as the between-subjects factor (group) and
the nine measurements during treatment as the
within-subjects factor (time). This was done for both
ADAS-cog and CDR-SB scores. To compare the
reduction in score of the ADAS-cog and CDR-SB
scales at week 16 in relation to baseline, an unpaired
two sided Student’s t-test was used. Fisher’s exact
test was employed to compare the baseline data and
frequency of adverse events between the protocols.
Results are presented as mean (SEM) and were
considered significant at a P-value of <0Æ05.
RESULTS
Figure 1 shows the trial profile. From January 2006
to June 2008, 82 patients were screened for the trial,
of whom 46 were randomized to either saffron or
placebo capsule. The last patient completed the
study in January 2009. There was no difference in
baseline characteristics including, gender, age,
duration of illness and education level (Table 1). In
the saffron and placebo group the number of
dropouts was 1, and 3, respectively.
Efficacy measures
ADAS-cog. The mean ± SEM scores of the two
groups of participants are presented in Fig. 2.
There were no significant differences between the
two groups at week 0 (baseline) on the ADAS-cog
rating scale (t=0Æ07, d.f. = 44, P=0Æ94). The
difference between the two groups was significant
as indicated by the effect of group, the between-
subjects factor (F=4Æ12, d.f. = 1, P=0Æ04). The
behaviour of the two treatments was not similar
over the trial period (groups-by-time interaction,
Greenhouse–Geisser correction; F= 204Æ43, d.f. =
3Æ63, P<0Æ0001). The difference between the two
groups was significant at week 16 (endpoint)
(t=4Æ16, d.f. = 44, P<0Æ0001). The changes at
week 16 compared to baseline were: )3Æ69 ± 1Æ69
(mean ± SD) and 4Æ08 ± 1Æ34 for saffron and
placebo, respectively. A significant difference was
observed on the change of scores of the ADAS-cog
rating scale at week 16 compared with week 0 in
the two groups (t=17Æ27, d.f. = 44, P<0Æ0001).
CDR-SB. The mean ± SEM scores of two groups
of participants are presented in Fig. 3. There were
no significant differences between the two groups
Fig. 1. Trial profile.
2010 The Authors. Journal compilation 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics
4S. Akhondzadeh et al.
at week 0 (baseline) on the CDR-SB (t=0Æ52,
d.f. = 44, P=0Æ60). The difference between the two
groups was significant as indicated by the effect of
group, the between-subjects factor (F=4Æ12,
d.f. = 1, P=0Æ04). The behaviour of the two
treatments was not similar over the trial period
(groups-by-time interaction, Greenhouse–Geisser
correction; F= 115Æ19, d.f. = 4Æ48, P<0Æ0001). The
difference between the two groups was significant
at week 16 (endpoint) (t=4Æ55, d.f. = 44,
P<0Æ0001). The changes at week 16 compared with
baseline were: )0Æ67 ± 0Æ24 (mean ± SD) and
0Æ63 ± 0Æ45 for saffron and placebo, respectively. A
significant difference was observed on the change
of scores of the CDR-SB at week 16 compared with
week 0 in the two groups (t=12Æ06, d.f. = 44,
P<0Æ0001).
Safety
There was one death in the placebo group because
of myocardial infarction. Five adverse events were
observed over the study. The difference between
the saffron and placebo in the frequency of adverse
events was not significant (Table 2). None of
adverse events was severe or caused a drop-out.
DISCUSSION
Alzheimer’s disease, a major public health problem,
is debilitating for patients and profoundly affects the
lives of their caregivers and loved ones adversely
Table 1. Baseline data Saffron
group
Placebo
group P
Gender Male: 13, female: 10 Male: 12, female: 11 ns
Age (mean ± SD) 72Æ65 ± 3Æ89 (year) 73Æ13Æ53 ± 4Æ70 (year) ns
Level of education Under diploma: 12,
diploma: 8,
higher diploma: 3
Under diploma: 13,
diploma: 7,
higher diploma: 3
ns
Time since
diagnosis
(mean ± SD)
20Æ30 ± 9Æ21(month) 19Æ17 ± 7Æ42(month) ns
Fig. 2. Mean ± SEM scores of the two protocols on the
ADAS-cog score. ns, non-significant.
Fig. 3. Mean ± SEM scores of the two protocols on the
CDR-SB score. ns, non-significant.
Table 2. Number of patients with adverse events
Adverse events Saffron (%) Placebo (%)P
Dizziness 2 (8Æ69) 3 (13Æ04) 1Æ00
Dry mouth 3 (13Æ04) 1 (4Æ34) 0Æ60
Fatigue 1 (4Æ34) 2 (8Æ69) 1Æ00
Hypomania 2 (8Æ69) 0 0Æ48
Nausea 2 (8Æ69) 1 (4Æ34) 0Æ25
2010 The Authors. Journal compilation 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics
Saffron in the treatment of Alzheimer’s disease 5
(1, 4). Considerable effort has therefore been devoted
to developing new and effective treatments. Treat-
ment strategies for AD include a variety on inter-
ventions directed at multiple targets. The available
approved medications for AD are often unsatisfac-
tory, and there may be a place for alternative medi-
cines, in particular herbal medicine (6).
Herbal medicine are still the mainstay of therapy
for approximately 75–80%of the world population,
mainly in the developing countries, in primary
health care because of better cultural acceptability,
and often better side-effects profiles. However,
during the last decade there has been a major
increase in their use in the developed world (31).
This study indicates that the saffron extract is
useful for the treatment of patients with mild to
moderate AD as shown by improvements in both
the ADAS-cog and CDR-SB measures. This is the
first study to evaluate saffron extract in the treat-
ment of patients with mild to moderate AD and so
it is not possible to draw any comparisons with the
results of other trials. Nevertheless, there is
increasing scientific evidence to suggest that saf-
fron may be useful in the management of AD (18,
21–24).
These studies showed that oral saffron extract
improved the memory of mice predamaged with
ethanol and that crocin prevents the inhibitory
effects of ethanol on LTP in mice (18, 21–24). Low
doses of saffron antagonized the extinction of
recognition memory in the object recognition test
and counteracted the scopolamine-induced
performance deficits in the passive avoidance task
(18). The results of this trial are consistent
with the results of those basic studies (18, 21–24)
as well as the reported antioxidant and antiamy-
loidogenic activity of an extract of saffron stigmas
(21).
Behavioural symptoms are common in AD and
are a major contributor to disease morbidity (32). In
AD, depression has been associated with more
rapid cognitive decline, increased caregiver
burden, increases in cost of patient-care as a result
of earlier institutionalization, greater use of medi-
cation, more frequent adverse side-effects and
more extensive institutional staffing needs (32).
Interestingly several basic studies and recent pub-
lished clinical trials have shown that saffron may
be antidepressant (14–16, 33), with frequency of
adverse events being was similar to that seen in
placebo groups. In our study, adverse events were
generally mild to moderate with no dropout as a
result of adverse events.
The limitations of present study include the
small number of patients and a relatively short
period of follow-up. Therefore, further randomized
controlled evaluation should be undertaken. The
use of herbal medicines in the treatment of AD
should be compared with the pharmacological
treatment currently in use. Therefore, comparison
with anticholinestrase inhibitors such as donepezil
would be interesting.
CONCLUSIONS
This study indicates that at least in the short-term
saffron is safe and effective in mild to moderate
AD. Larger and longer randomized controlled
studies are required to further validate this herbal
remedy.
ACKNOWLEDGMENTS
This study was supported by two grants from
Tehran University of Medical Sciences and Green
Plants of Life Co, IMPIRAN to Prof. Shahin
Akhondzadeh (Grant No: 4843).
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8S. Akhondzadeh et al.
... Some health and well-being applications have been demonstrated in the literature. Health benefits of saffron have been suggested for the treatment of anxiety disorders [6][7][8], premenstrual syndrome [9], neurodegenerative retinal diseases [10], erectile disorders [11], and for mental health [12][13][14][15]. The saffron market for food supplements is constantly growing, with hydroalcoholic extracts marketed in capsules, tablets, or other galenic formulations. ...
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Article
Saffron is a very high value-added ingredient used in the food supplement market and contains a high level of safranal. Adding synthetic safranal to saffron, which is significantly cheaper, and falsifying the origin of saffron may represent recurrent fraud. Saffron from different countries was analyzed to determine the stable isotope ratios δ13C and δ2H from safranal by gas chromatography coupled with isotope-ratio mass spectrometry (GC-C/P-IRMS) and the concentration of saffron metabolites with ultra-high performance liquid chromatography coupled with diode array detector (UHPLC-DAD). The isotopic analysis highlighted a higher ratio of δ2H in synthetic safranal than in natural safranal; the mean values were 36‰ (+/− 40) and −210‰ (+/− 35), respectively. The δ13C between Iranian, Spanish and other saffron was significantly different and represents median values of −28.62‰, −30.12‰ and −30.70‰, respectively. Moreover, linear and quadratic discriminant analyses (LDA and QDA) were computed using the two isotope ratios of safranal and the saffron metabolites. A first QDA showed that trans-crocetin and the δ13C of safranal, picrocrocin, and crocin C3 concentrations clearly differentiated Iranian saffron from other origins. A second model identified δ13C, trans-crocetin, crocin C2, crocin C3, and picrocrocin as good predictors to discriminate saffron samples from Iran, Spain, or other origins, with a total ability score classification matrix of 100% and a prediction matrix of 82.5%. This combined approach may be a useful tool to authenticate the origin of unknown saffron.
... Those in the saffron group received 15 mg of saffron capsules twice daily. The saffron extract preparation method is detailed elsewhere (Akhondzadeh et al., 2010). In the placebo group, participants received starch-based placebo capsules, identical to the saffron capsules, twice daily. ...
Article
Objective: One of the traditional aphrodisiacs used in various cultures is Crocus sativus, commonly called saffron. Previous studies have pointed to the possible applicability of saffron for sexual dysfunction in both men and women. This study investigates the effects of saffron capsules on female sexual dysfunction. Materials and methods: This study was a parallel-group, double-blind, randomized, placebo-controlled clinical trial. Participants, who were married women between 18 and 55 years of age suffering from severe sexual dysfunction, were randomized to receive either 15 mg Crocus sativus capsules twice daily or placebo. The treatment continued for 6 weeks, and patients were evaluated every 2 weeks. The primary outcome was the change in the female sexual function index score. Other outcomes included the female sexual function index sub-domains. Results: Seventy -four patients were equally randomized to each group, and 34 in each group completed the trial. Participants in both groups experienced improved total scores at each visit. However, a repeated-measures ANOVA revealed that time treatment differed between groups in favor of the saffron group (p=0.050). During the 6th week follow-up, the saffron group had a 62% score improvement from baseline. Desire, lubrication, and satisfaction were female sexual function index domains in which saffron demonstrated superiority over placebo. The adverse event profile was similar for the groups, and no participant discontinued treatment. Conclusion: Findings of this study suggest that saffron might be a safe and effective option to ameliorate female sexual dysfunction. Further robust research is warranted.
... (15 mg, BID) on patients in comparison with those who received a placebo. The efficacy of saffron in this study, after shorter duration of treatment, was surprisingly more than in the aforementioned trial and unlike it, the cognitive profiles of cases were significantly better than the baseline in the saffron group (25). The alleviating effects of saffron on mild cognitive impairment were also demonstrated by another one-year clinical study; however, it has several serious weak points, the most important of which include not mentioning the amount of saffron administered, no placebo group, small sample size (35 subjects), and no randomized grouping (26). ...
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Article
Saffron, the stigmas of Crocus sativus L., has been mentioned extensively in the traditional reference texts as a herbal medicine. Many clinical trials have been conducted on this valuable herbal substance and its main constituents following numerous cellular and animal assessments. In the present review, we have collected almost all of these clinical studies to clarify how much knowledge has clinically been achieved in this field so far and which scientific gaps are needed to be filled by more studies. A comprehensive literature review was conducted through a two-round search. First, we performed a general search for identifying the human disorders against which saffron was studied. Then, we searched specifically for the combination of saffron keywords and each disease name. Scientific databases including Scopus, PubMed, and Web of science were used for this search. Studies were collected through electronic databases from their inception up to August 2021. The largest number of these clinical studies represent the investigations into saffron efficacy in different neurological and mental disorders, particularly depression. This substance has clinically revealed significant protective effects against various types of depression, age-related macular degeneration, and allergic asthma. In some cases, such as sexual dysfunction, cognitive and metabolic disorder, the effects of saffron are still clinically open to dispute, or there are limited data on its positive influences. Overall, saffron and its constituents have promising effects on human disorders; however, it needs more clinical evidence or meta-analyses to be confirmed.
... Psychometric measures revealed that patients treated with saffron improved cognitive function after 16 weeks. In adverse event reports between the two groups, there was no significant difference proving that saffron is safe and effective in treating mild to moderate Alzheimer disease [105]. ...
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Article
The present review is designed to measure the effects of saffron extract in functional foods and its pharmacological properties against various disorders. Saffron is a traditional medicinal plant that is being used as food additive. The stigma of saffron has bioactive compounds such as safranal, crocin, crocetin, picrocrocin, kaempferol and flavonoid. These bioactive compounds can be extracted using conventional (maceration, solvent extraction, soxhlet extraction, and vapor or hydro-distillation) and novel techniques (emulsion liquid membrane extraction, ultrasound-assisted extraction, enzyme-associated extraction, pulsed electric field extraction, microwave-assisted extraction and supercritical fluid extraction). Saffron is used as a functional ingredient, natural colorant, shelf-life enhancer, and fortifying agent in developing different food products. The demand for saffron has been increasing in the pharma industry due to its protection against cardiovascular and Alzheimer's disease and its antioxidant, anti-inflammatory, antitumor and antidepressant properties. Conclusively, the phytochemical compounds of saffron improve the nutrition value of products and protect humans against various disorders
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With the rapid increase in life expectancy and the proportion of the elderly population, the global prevalence of various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and Huntington's disease, is rising dramatically. The demographic trend of the aged population has attracted people's attention to the discovery and treatment of new drugs for age-related diseases. Currently, there are various drugs and treatments available for the treatment of neurodegenerative diseases, but side effects or insufficient drug efficacy have been reported. With a long history of herbs or natural compounds used in the treatment of age-related diseases, new evidence has been reported to support the pharmacological effects of Indopathy in ameliorating symptoms or interfering with the pathogenesis of neurodegenerative diseases. Many Indian medicinal plants have been used for thousands of years in Indopathy. Amongst these are plants used for the management of neurodegenerative diseases, such as Parkinson's, Alzheimer's, loss of memory, degeneration of nerves, and other neuronal disorders by Ayurvedic practitioners. Though the etiology of neurodegenerative diseases remains enigmatic, there is evidence indicating that defective energy metabolism, excitotoxicity, and oxidative damage may be crucial factors. This book summarizes the new therapeutic leads from herbal sources for various types of neurodegenerative diseases. Based on recent research, this volume makes an effort to utilize existing knowledge of some popular medicinal plants, and their biologically active components have been discussed, especially those used in Indopathy. Several promising plants such as Withania somnifera, Bacopa monnieri, Centella asiatica, and Mucuna pruriens are worth exploring for the development of neuroprotective drugs.
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Neurodegenerative diseases (NDs) are characterized by progressive neuronal loss (structurally and/or functionally) in different regions of the brain. NDs represent one of the most important public health concerns, as they are the growing cause of death around the world, especially among the elderly. Aging has led to an increase in NDs, such as Alzheimer's disease, dementia, cerebrovascular impairment, seizure disorders, head injury, and Parkinson's disease, which are becoming critical due to their irreversibility, lack of effective medication, and the resulting social and financial burdens. Indeed, despite the noteworthy achievements in our understanding of NDs, there has been little achievement in formulating suitable therapies. Currently, the available treatments for NDs seem to be ineffective, as they only work to ease the symptoms but cannot prevent the disease's progression. The use of medicinal herbs is emerging as an alternative or integrative therapeutic against NDs because of the preconception that medicinal herbs are consequently safe. Phytochemicals from medicinal plants assume an indispensable job in keeping up the chemical balance of the brain by affecting the capacity of receptors for the major inhibitory neurotransmitters. In a conventional act of medication, a few plants have been accounted for to treat NDs. This volume highlights various homegrown medications and their scientific validation to maintain neuronal wellbeing, utilized in Ayurveda practices and Chinese medication. This book summarizes different phytochemicals from various medicinal herbs that are used as promising therapeutic agents for NDs due to their anti-inflammatory and anti-oxidative as well as anticholinesterase activities. Even though the affinity of receptors or carriers for polyphenols or different phytochemicals of the homegrown arrangements in cerebrum tissues remains to be found out, numerous candidates show up as a potential and promising class of therapeutics for the treatment of ailments with a multifactorial etiology. Adopting the ethnomedicinal approach, this book addresses the intersection between recent therapeutics for NDs and personalized medicine that will allow a broader range of interventions, including evidence-based natural products.
Chapter
Crocus sativus L. or Saffron is the most expensive spice in the world and is also used as a coloring and flavoring agent. In several cultures and civilizations, saffron is known for its various therapeutic properties. Research in ethnobotany and ethnopharmacology focuses on the medicinal potential of plants in several populations and a better understanding of the use of plants by humans. The exploitation of these data can help in the development of new modern drugs and alternative therapeutic approaches. The healing and culinary peculiarities of saffron are related to the presence of four major bioactive compounds, which are crocin, crocetin, picrocrocin, and safranal. In this current chapter, we discuss therapeutic applications of saffron mainly linked to the abundant metabolites. A large number of studies reported the antioxidant potential of saffron, which involves its antitumor, anti-inflammatory, and neuroprotective effects. Moreover, a neuroprotective activity of saffron was widely assessed in neurodegenerative diseases like depression, Alzheimer, and schizophrenia, and is particularly attributed to safranal and crocin. We have also noted the therapeutic potential of crocin in neuro-inflammatory diseases and the antibacterial activity of saffron against a few clinical strains. However, the use of saffron must be done with great care to avoid any possible toxicity.Keywords Saffron Crocus sativus L. Metabolites Crocin Safranal Therapeutic application Neuroprotective effects
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.
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The prevalence of both Alzheimer's disease (AD) and diabetes mellitus is increasing with the societies' aging and has become an essential social concern worldwide. Accumulation of amyloid plaques and neurofibrillary tangles (NFTs) of tau proteins in the brain are hallmarks of AD. Diabetes is an underlying risk factor for AD. Insulin resistance has been proposed to be involved in amyloid-beta (Aβ) aggregation in the brain. It seems that diabetic conditions can result in AD pathology by setting off a cascade of processes, including inflammation, mitochondrial dysfunction, and ROS and advanced glycation end products (AGEs) synthesis. Due to the several side effects of chemical drugs and their high cost, using herbal medicine has recently attracted attention for the treatment of diabetes and AD. Saffron and its active ingredients have been used for its anti-inflammatory, anti-oxidant, anti-diabetic, and anti-AD properties. Therefore, in the present review paper, we take account of the clinical, in vivo and in vitro evidence regarding the anti-diabetic and anti-AD effects of saffron and discuss the preventive or postponing properties of saffron or its components on AD development via its anti-diabetic effects.
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Article
Alzheimer's disease (AD) is the common type of dementia and is currently incurable. Existing FDA-approved AD drugs may not be effective for everyone, they cannot cure the disease nor stop its progression and their effects diminish over time. Therefore, the present review aimed to explore the role of natural alternatives in the treatment of AD. A systematic search was conducted using Ovid MEDLINE, CINAHL, Cochrane and PubMed databases and reference lists up to November 30, 2021. Only randomized control trials were included and appraised using the National Institute of Health framework. Data analysis showed that herbs like Gingko Biloba, Melissa Officinalis, Salvia officinalis, Ginseng and saffron alone or in combination with curcumin, low-fat diet, NuAD-Trail, and soy lecithin showed significant positive effects on AD. Moreover, combination of natural and pharmaceuticals has far better effects than only allopathic treatment. Thus, different herbal remedies in combination with FDA approved drugs are effective and more promising in treatment of AD.
Article
Depression is a serious disorder in today's society. With estimates of lifetime prevalence as high as 21% of the general population in some developed countries. As a therapeutically plant, saffron it is considered an excellent stomach ailment and an antispasmodic, helps digestion and increases appetite. It is also used for depression in Persian traditional medicine. Our objective was to assess the efficacy of stigmas of Crocus sativus (saffron) in the treatment of mild to moderate depression in a 6-week double-blind, placebo controlled and randomized trial. Forty adult outpatients who met the Diagnostic and Statistical Manual of Mental Disorders, 4th edition for major depression based on the structured clinical interview for DSM IV participated in the trial. Patients have a baseline Hamilton Rating Scale for Depression score of at least 18. In this double-blind, placebo controlled, single-center trial and randomized trial, patients were randomly assigned to receive capsule of saffron 30 mg/day (BD) (Group 1) and capsule of placebo (BD) (Group 2) for a 6-week study. At 6 weeks, Crocus sativus produced a significantly better outcome on Hamilton Depression Rating scale than placebo (d.f.=1, F= 18.89, p<0.001). There were no significant differences in the two groups in terms of observed side effects. The results of this study indicate the efficacy of Crocus sativus in the treatment of mild to moderate depression. A large- scale trial is justified.
Article
Published research in English-language journals are increasingly required to carry a statement that the study has been approved and monitored by an Institutional Review Board in conformance with 45 CFR 46 standards if the study was conducted in the United States. Alternative language attesting conformity with the Helsinki Declaration is often included when the research was conducted in Europe or elsewhere. The Helsinki Declaration was created by the World Medical Association in 1964 (ten years before the Belmont Report) and has been amended several times. The Helsinki Declaration differs from its American version in several respects, the most significant of which is that it was developed by and for physicians. The term "patient" appears in many places where we would expect to see "subject." It is stated in several places that physicians must either conduct or have supervisory control of the research. The dual role of the physician-researcher is acknowledged, but it is made clear that the role of healer takes precedence over that of scientist. In the United States, the federal government developed and enforces regulations on researcher; in the rest of the world, the profession, or a significant part of it, took the initiative in defining and promoting good research practice, and governments in many countries have worked to harmonize their standards along these lines. The Helsinki Declaration is based less on key philosophical principles and more on prescriptive statements. Although there is significant overlap between the Belmont and the Helsinki guidelines, the latter extends much further into research design and publication. Elements in a research protocol, use of placebos, and obligation to enroll trials in public registries (to ensure that negative findings are not buried), and requirements to share findings with the research and professional communities are included in the Helsinki Declaration. As a practical matter, these are often part of the work of American IRBs, but not always as a formal requirement. Reflecting the socialist nature of many European counties, there is a requirement that provision be made for patients to be made whole regardless of the outcomes of the trial or if they happened to have been randomized to a control group that did not enjoy the benefits of a successful experimental intervention.
Article
Various active compounds derived primarily from Oriental and European medicinal plants, including Ginkgo biloba, Panax ginseng, Nicotiana tobaccum, Huperzia serrata, Galanthus nivalis and Salvia officinalis, have been assessed for their efficacy in dementia, primarily in Alzheimer’s disease. These plants may be used individually or, particularly in traditional Chinese or Ayurvedic formulations, in combination. The mechanisms of action of medicinal plant extracts in Alzheimer’s disease have yet to be fully determined, but are thought to involve anticholinesterase, anti-inflammatory, antioxidant and estrogenic activity, and cholinergic receptor activation. Robust clinical trial data are currently scarce. However, those that are available confirm the effectiveness of G. biloba in delaying deterioration or inducing symptomatic improvement in patients with Alzheimer’s disease. In addition, the extract does not appear to be associated with adverse or toxic effects. The active component of G. nivalis, the selective acetylcholinesterase inhibitory alkaloid galantamine (galanthamine), is currently commercially available in Austria and is preregistrational in a number of other countries for the symptomatic treatment of mild/moderate Alzheimer’s disease. Currently available data indicate galantamine to be well tolerated in the long term, with a relative lack of toxicity at clinically effective dosages. Future development of effective novel therapeutic strategies for dementia may benefit from the combination of conventional Western medical science and traditional Oriental medical practices.
Article
The acute effects of crocin and picrocrocin, major components of Crocus Sativus L., on learning and memory performances were investigated using mice in passive avoidance tasks. A single oral administration of crocin had no effect on memory acquisition in normal mice. Oral administration of 30% ethanol (10ml/kg) induced impairment of memory acquisition in step through and step down tests. Oral pre-administration of crocin (50 to 200mg/kg) improved the impairment of memory acquisition in both tests in a dose-dependent manner. Crocin (50 to 200mg/kg) also had beneficial effect on 40% ethanol (10mg/kg, p.o.)-induced memory retrieval deficit in step down test. Picrocrocin, the most abundant component in Crocus Sativus L., did not affect the impairment of memory acquisition and retrieval in step through and step down tests at 50-200mg/kg. These results suggest that crocin has preventive effect on the ethanol-induced impairment of learning and memory.
Article
Various active compounds derived primarily from Oriental and European medicinal plants, including Ginkgo biloba, Panax ginseng, Nicotiana tobaccum, Huperzia serrata, Galanthus nivalis and Salvia officinalis, have been assessed for their efficacy in dementia, primarily in Alzheimer's disease. These plants may be used individually or, particularly in traditional Chinese or Ayurvedic formulations, in combination.The mechanisms of action of medicinal plant extracts in Alzheimer's disease have yet to be fully determined, but are thought to involve anticholinesterase, anti-inflammatory, antioxidant and estrogenic activity, and cholinergic receptor activation. Robust clinical trial data are currently scarce. However, those that are available confirm the effectiveness of G. biloba in delaying deterioration or inducing symptomatic improvement in patients with Alzheimer's disease. In addition, the extract does not appear to be associated with adverse or toxic effects. The active component of G. nivalis, the selective acetylcholinesterase inhibitory alkaloid galantamine (galanthamine), is currently commercially available in Austria and is preregistrational in a number of other countries for the symptomatic treatment of mild/moderate Alzheimer's disease. Currently available data indicate galantamine to be well tolerated in the long term, with a relative lack of toxicity at clinically effective dosages.Future development of effective novel therapeutic strategies for dementia may benefit from the combination of conventional Western medical science and traditional Oriental medical practices.
Article
The effect of an ethanol extract of Crocus sativus L. (CSE) on the long-term potentiation (LTP) of the evoked potential in the dentate gyrus of the hippocampus was investigated using anaesthetized rats. CSE (250 mg/kg, p.o.) alone did not affect the generation of LTP by application of subthreshold or suprathreshold tetanic stimulation (20 or 30 pulses at 60 Hz). Oral administration of ethanol (10–30%, 10 mL/kg) blocked the LTP induced by tetanic stimulation of 30 pulses at 60 Hz, but the LTP-blocking effect of ethanol was significantly attenuated by pre-administration of CSE (125 and 250 mg/kg, p.o.). The blockade of LTP induction by intravenously injected ethanol (30%, 2 mL/kg) was also antagonized by administration of CSE at doses of 125 and 250 mg/kg (p.o.). Oral administration of CSE antagonized also the LTP-blocking effect of ethanol directly injected into the brain, although it required a higher dose (500 mg/kg, p.o.). These results suggest that oral administration of CSE exerts an antagonistic effect on ethanol-induced impairment of hippocampal synaptic plasticity, which is possibly mediated by both direct action on the central nervous system and peripheral action.