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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.Jamshidi–PhD,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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