Key words
Crocus sativus - clinical - saffron - crocin - safranal
Introduction
Crocus sativus L (commonly known as saffron) is a perennial stemless herb from the Iridaceae family
that is largely cultivated in Iran and some other countries including Spain, India
and Greece [1]. C. sativus grows up to 20–30 cm height and has 5–11 true leaves that are shielded and covered
by 5–11 non-photosynthetic and white leaves (cataphylls). In October, the plant blooms
striped purple with a honey-like smell [2].
Important constituents of saffron that are pharmacologically active are bitter principles
(e. g. picrocrocin), volatile agents (e. g. safranal), and dye materials (e. g. crocetin
and its glycoside crocin) [1].
Although research into effects of saffron is not a new subject and ancient Persian
literatures recommend using saffron as a medicine for treating several diseases, the
number of cited documents in medical databases such as Scopus® have increased over the last 20 years, most of them (78.51%) being original research.
Furthermore, the first record being cited with the keywords of “saffron+clinical trial”
in Scopus® belongs to the publications of 1998. The number of such papers has been increased
through 2004–2012, 62% of which being original clinical trials (32 papers). However,
66 countries were cited for the authors’ affiliations of the cited documents in Scopus® with the keyword “saffron”. Most articles were published by the Iranian and Spanish
researchers (22.3% by Iranian and 10.7% by Spanish authors) and more than one-third
of the clinical trials were documented by the Iranian scientists (37.3%).
Several useful pharmacological effects of saffron or its active components have been
shown in animal studies along with the few clinical trials, including: anticonvulsant
[3]
[4], antidepressant [5]
[6], anti-inflammatory [7]
[8], antitumor [9], radical scavenger effects [10] and learning and memory improving [11]
[12]
[13]. Protective effects of saffron extracts on goenotxins-induced oxidative stress have
been reported [14]
[15]. There are numerous studies about antioxidant effects of saffron or its ingredients
[12]
[16]
[17]. It has been also shown that saffron can promote the diffusivity of oxygen in different
tissues [17]. A number of investigations into safety and toxicity of saffron and its components
have been conducted [18]
[19]
[20]
[21] and some clinical trials about different pharmacological effects of saffron can
be found in literatures. In this review, we have discussed strengths and weaknesses
of the aforementioned studies.
Pharmacokinetics
Pharmacokinetic evaluation of crocin and crocetin has been carried out in animal and
human studies. Pharmacokinetic study of crocin, an active compound of saffron, in
mice showed that it could not be absorbed through the gastrointestinal tract after
either a single dose or repeated doses [22]. Crocin was largely excreted from the intestinal tract following oral administration
[23]. It is hydrolyzed to crocetin before absorption through gastro-intestinal tract
[22]
[24].
Crocetin is quickly absorbed after oral administration to mice. It can be detected
in plasma in free form as well as in the form of a glucuronic acid conjugate [22]. In rats, a single oral dose of 50 mg/kg crocetin has been shown to have t½=30±6 min,
tmax=65±16 min, Cmax=5.0±1.0 μg/ml, AUC=845±109 μg×min/ml, and Vd=5.0±0.8 l/kg [23]. The short plasma half-life of crocetin results in rapid elimination without being
accumulated in the body [23]
[25]. Crocetin concentrations in rats’ plasma did not tend to accumulate with the repeated
doses of oral crocin [23]
[24]. The concentration-time curve of crocetin has been fitted with a 2-compartment open
model after intravenous administration to rabbit [26].
Umigai and colleagues investigated pharmacokinetic profile of crocetin in healthy
adult volunteers (5 men and 5 women) in an open-label, single dose escalation study
[27]. Every individual consumed a single dose of crocetin at 3 doses (7.5, 15 and 22.5 mg)
with one week intervals. Crocetin was rapidly absorbed in animal studies as well,
and could be detected within an hour of administration, reaching to the maximum concentration
in 4.0–4.8 h (Tmax) [27]. Additional important pharmacokinetic parameters of crocetin were as follows: Cmax=100.9–279.7 ng/ml, AUC0–24 h=556.5–1720.8 ng.h/ml, T1/2 (h)=6.1±7.2 to 7.5±2.8, CL/F (l/h)=12.8±2.9 to 13.8±5.4 and Vd/F (l)=82.8±59.0 to
152.6±80.1 [27]. These parameters had no significant disparity in different doses, except for Cmax and AUC0–24 h, which showed a dose dependent correlation [27].
Safety and Toxicity
Saffron is being used as a food additive for several centuries and this supports its
safety for most people. Administrated as medicine, saffron toxicity and safety required
an evaluation.
Intraperitoneal LD50 values of saffron stigma and petal are reported to be 1.6 and 6 g/kg in mice, respectively
[28]. Nevertheless, it is not toxic when administrated orally with LD50 value being above 5 000 mg/kg. [19]. Although ingestion of less than 1.5 g of saffron is nontoxic for human [1], it is considered toxic when ingested with doses more than 5 g and could be lethal
if taken about 20 g/day [1]
[29]. Given that the common effective doses being applied in clinical trials are considerably
lower than this level (30–50 mg/day), saffron has a wide therapeutic index.
Mild toxicity with saffron induce dizziness, nausea, vomiting and diarrhea while a
more severe toxicity can cause numbness, tingling in the hands and feet, and yellowish
skin and eyes due to precipitation of yellow pigments on the skin and conjunctiva.
Spontaneous bleeding may be a symptom as well [28]
[30]
[31].
A randomized, double-blind, placebo-controlled clinical trial (RDBPCCT) study by Mansoori
et al. [18] evaluated the safety of saffron administration on sexual dysfunction in 20 adult
patients suffering from major depressive disorder (MDD). The individuals were divided
into 2 groups receiving either 15 mg capsules of saffron or placebo twice daily. Laboratory
tests including liver and renal function tests, blood cell count and coagulation tests,
were assessed once before the trial and then in 4 weeks. No major laboratory changes
were observed in patients receiving saffron, providing evidences for the safety of
this herbal medicine [18].
Mohamadpour and colleagues, designed a RDBPCCT for safety of crocin tablets (20 mg)
in 22 men and women during 1 month [32]. Also, Modaghegh et al. have evaluated the safety of taking 200–400 mg tablets of
ethanolic extraction of saffron, nearly 4–10 times higher than the recommended therapeutic
doses, for 1 week in a RDBPCCT on 30 healthy adults with normal appearance [28]. Saffron did not show any considerable adverse effects on blood pressure except
for decreasing the standing systolic blood pressure and mean blood pressure. They
reported no changes in the EKG of the participants [28]. Neither saffron nor crocin have had any dose-dependent effect on reducing RBC parameters
[28]
[32].
Saffron has been shown to reduce platelet counts at dose of 200 mg/day [28]. However, in 2 different studies, Mansoori et al. and Mohamadpour et al., showed
a non-significant reduction in such parameters [18]
[32]. In animal models, saffron was able to increase coagulation time in mice, and inhibit
platelets aggregation in rabbit. These effects of saffron seem to be not related to
crocin and safranal, but to adenosine [28]
[33]. Crocin tablets could have significantly reduced partial tromboplastin time but
had no significant effect on prothrombin time [32].
However, crocin in subchronic administration in animal models is shown to reduce levels
of serum total cholesterol, triglyceride and low-density lipoprotein cholesterol;
inhibit the formation of aortic plaque and have anti-atherosclerosis effect due to
antioxidant properties [34]
[35]. There was no change in the lipid profile of individuals ingesting saffron in Modaghegh
et al. study [28]. Mohamadpour also reported insignificant changes in lipid profile of patients who
were treated with crocin in comparison with control [32]. Nevertheless, diet programs of groups in the 2 mentioned studies did not match.
Administration of 200 and 400 mg/day of saffron for 1 week elevated creatinine (Cr)
and blood urea nitrogen (BUN) levels [28]. However, Mansoori et al. did not report any changes in the renal parameters 4 weeks
following the ingestion of 30 mg/day of ethanolic extract of saffron, and so did Mohamadpour
et al. [18]
[32]. This difference seems to be related to the dose and the sampling time. Renal toxicity
of saffron has also been mentioned in traditional medicine [18]. Mohajeri et al. reported that the intraperitoneal administration of the ethanolic
extract of saffron to rats in doses of 0.35, 0.70 and 1.05 g/kg BW for 2 weeks, significantly
increased levels of BUN and Cr [21]. In 2 studies by Mohammadpour and Mansoori, clearance of Cr or more accurate renal
function parameters had not been calculated.
Mohamadpour and colleagues reported no important difference in serum electrolytes
parameters (such as calcium and phosphorus), liver function tests and hormone levels
(thyroxine, thyroid-stimulating hormone, cortisol and testestron) between placebo
and crocin-treated (2 mg/d) groups [32]. Serum concentrations of crocin and crocetin had not been reported by any of the
mentioned studies.
Given that the majority of crocin is not absorbed via gastrointestinal tract, it
might have given a better estimation of pharmacokinetic-pharmacodynamic relationship
for crocin, if researchers had evaluated serum levels of crocin or crocetin.
In some of the clinical trials about the efficacy of saffron in the Alzheimer disease
and depression, 15–30 mg/day of saffron capsule were prescribed and several minor
adverse effects such as nausea, vomiting, dizziness, dry mouth and etc. have been
reported. The commonest adverse effect of saffron was dry mouth (18 and 13%) [36]
[37]
[38]
[39]. In a report by Modaghegh and colleagues in which they had treated their precipitance
with higher doses, no minor adverse effects were mentioned. Such differences in these
studies are probably related to the duration of treatment. Gout reported a few minor
adverse effects such as nausea, diarrhea, and reflux in about 16% of volunteers; the
overweight women receiving 174.5 mg/day of saffron for 8 weeks. These side effects
were no more than the placebo group [40]. On the other hand, it may be associated with recall bias in neurologic clinical
trials in which researchers mentioned similar instances of adverse effects. The authors
reported no significant difference between saffron and placebo regarding the side
effects. Correlation between advancing age and rate of adverse drug reaction has been
shown in some studies [41] and it may be another reason for such variation. For instance, the average age in
Modaghegh’s study (27.4–30 years) was lower than that in neurologic clinical trials
(35–73years). Modaghegh et al. reported abnormal uterine bleeding in one female in
each group of 200 and 400 mg of saffron. As documented in traditional medicine, saffron
had been used for abortion [39], and later in was shown to be able to induce uterine stimulants and have estrogenic
effects in guinea pigs and mice, respectively [42]. This type of side effects were not described in Gout’s study on 60 women with doses
near to that of Modaghegh’s study but with extended duration [40].
We could not find any study on the interactions between different drugs and saffron.
However, in patients under anticoagulant therapy or those having certain types of
renal insufficiency, a cautious approach for prescribing saffron is suggested.
Cardiovascular
The effects of crocin, an active constituent of C. sativus, have been studied in isoproterenol-induced cardiotoxicity in rats [43]. Either crocin (5, 10 and 20 mg/kg/day) or vehicle were administered orally for
21 days together with isoproterenol (85 mg/kg, subcutaneously, every 24 h) on the
last 2 days in order to induce cardiac dysfunction, which was indicated as low blood
pressure. The results illustrated a possible cardioprotective effect for crocin in
isoproterenol-induced cardiac toxicity via modulating oxidative stress resulted in
maintaining the redox status of cells [44].
It has been shown that the aqueous extract of saffron stigma has hypotensive effect
in rats, which is partly due to the actions of its 2 major constitutes, crocin and
safranal; taking into account that safranal plays a greater role in decreasing the
blood pressure in comparison to crocin [45].
In RDBPCCT used saffron tablets for one week on 30 healthy volunteers divided into
3 groups of placebo, 200 and 400 mg saffron. The results demonstrated that saffron
at dose of 400 mg could significantly decrease standing systolic blood pressure and
mean arterial pressures and increase serum sodium, BUN and Cr. The biochemical changes
were within the normal ranges and turned out to be clinically insignificant [28]. In addition, it has been shown that aqueous-ethanolic extract of saffron has a
potent inhibitory effect on calcium channels of guinea pig isolated heart [46].
It has long been revealed that crocetin can almost completely prevent the induced
atherosclerosis in rabbits, most likely through increasing the oxygenation of tissues
[47]. In another study on rabbits, in which 2 out of 3 groups of animals received either
high lipid diet alone or high lipid diet plus crocetin, crocetin was shown to have
anti-atherosclerotic effect since it suppressed the expression of vascular cell adhesion
molecule-1 (VCAM-1), which might be due to deactivation of NF-kappa B [48]. However, there have been reports that the incidence of cardiovascular diseases
is noticeably lower in the geographic parts where saffron is used in daily diet of
inhabitants [49], taking into account that antioxidants and flavonoids, especially lycopene, that
exist in saffron are proven to decrease the risk of cardiovascular diseases [50].
A clinical trial was held by Verma et al., showed the prospective effects of saffron
on cardiovascular disorders. In this study, 50 mg of saffron was dissolved in 100 ml
of milk and administered twice a day to 20 individuals, 10 of them suffering from
heart disease. A constant decrease in lipoprotein oxidation susceptibility was investigated
after 3 and 6 weeks; hence, the significant drop in LOS levels indicated a potential
antioxidant effect for saffron [51].
Taking into account the anti-atherosclerotic, antioxidant, anti-diabetes, hypotensive,
anti-ischemic, anti-platelet aggregation and hypolipidemic effects of saffron, this
herb can be considered as a promising treatment in decline of cardiovascular risk
factors.
Neuropsychology
Alzheimer disease
Alzheimer disease (AD) is the most frequent form of dementia [52]. It is estimated that 42 million people worldwide will suffer from AD by 2040 [53] and it will reach epidemic proportions. Diagnosis of AD is based on criteria and
symptoms. The most common symptom pattern begins with a gradually worsening difficulty
in remembering new information [53]. Few drugs have been developed to alleviate these cognitive symptoms, thus more
practical and safe medications are required for the cognitive, behavioral and psychological
symptoms of dementia [54].
Crocin and safranal are shown to inhibit the formation of soluble oligomers and following
fibrillar assemblies in cell culture. It is assumed that they bind to hydrophobic
patches provided in the intermediate structures and thereby inhibit protein aggregation.
The simultaneous hydrophobic and hydrophilic properties of crocin result in a more
effective action [54]. Due to antioxidant properties of C. sativus stigma constituents [13]
[56], they are effective in Abeta fibrillogenesis and deposition in a concentration and
time-dependent manner [57]. Abeta fibril formation and deposition is thought to be promoted by oxidation [57]. Diffuse and neurotic extracellular amyloid plaques and intracellular neurofibrillary
tangles in the hippocampus, cerebral cortex and other areas of the brain, that are
essential for cognitive function, is considered to be associated with AD and other
neurodegenerative disorders such as Parkinson disease [53]
[55]
[58].
Chronic microglial activation produces various pro-inflammatory and neurotoxic factors
that induce neuronal injury [7]; therefore, negative regulation of microglial activation is an alternative to treat
neurodegenerative disorders. In cultured microglial cells of rat brain, crocin and
crocetin could inhibit LPS-induced nitric oxide (NO) release and result in reducing
tumor necrosis factor-alpha, interleukin-1beta, and intracellular reactive oxygen
species, as well as showing neuroprotection effect and inhibiting the hippocampal
cells death [7].
Shams and colleagues reported that aqueous extract of saffron can improve learning
and memory. Their results also indicated that aqueous extract of saffron increases
brain dopamine and glutamate concentrations, whereas it could change neither brain
serotonin nor norepinephrine [58]. The effectiveness of saffron extract and crocin on memory enhancing in chronic
cerebral hypoperfusion in rat has been reported [16]. It was reported that administration of C. sativus extracts could antagonize ethanol, acetaldehyde and scopolamine-induced memory impairment
in rat and mouse [10]
[13]
[59]
There are 2 clinical trials on patients with mild-to-moderate AD [36]
[37], the first one being a 16-week, RDBPCCT [36] and the second being a 22-week, multicenter, RDBPCCT [37]. On both studies, diagnosis of AD was based on the criteria of Diagnostic and Statistical
Manual of Mental Disorders. Efficacy of treatment was evaluated by changing in AD
Assessment Scale and cognitive subscale and Clinical Dementia Rating Scale. Akhondzadeh
et al. treated patients with dose of 30 mg/day (15 mg twice a day) of saffron or placebo
for 16 weeks in first, and also with either 30 mg/day saffron capsules (15 mg twice
a day) or donepezil 10 mg/day (5 mg twice a day) for 22 weeks in the second study
[36]
[37]. Authors reported that saffron produced a significantly superior outcome on cognitive
function than the placebo. They also showed that the effectiveness of saffron on improving
the cognition score of AD patients was equal to that of donepezil, both decreasing
the score in Alzheimer’s Disease Assessment Scale by about 3.7, and the score of Clinical
Dementia Rating Scale by 0.7–0.8. Although saffron was shown to possess adverse effects,
they were no more than the placebo or donepezil.
Both studies were designed very well as multicenter double-blind clinical trials,
although they did not completely define the etiology in their patients [36]
[37]. Prescribing saffron for AD patients requires more extended studies with bigger
sample size and different types of etiologies.
Depression
Depression is the fourth cause of disability worldwide [60]. In Persian traditional medicine, saffron is used for depression [62]. Hosseinzadeh et al. reported the antidepressant effect of C. sativus stigma extracts as well as safranal and crocin in mice being assessed by forced swimming
test. Safranal (0.15–0.5 ml/kg) and crocin (50–600 mg/kg) could reduce the immobility
time, and both extracts increased swimming time similar to fluoxetine and increased
climbing time like to imipramine [61]. It seems that crocin may inhibit uptake of dopamine and norepinephrine, and safranal
acts via serotonin [6]
[61]. There are some other papers about effectiveness of saffron against depression on
different animal models [5]
[63]
[64]. Saffron has also been reported to have anxiolytic effects in animal models [65].
C. sativus extract has been used in some antidepressant clinical trials ([Table 1]). The antidepressant effects of saffron were compared with placebo in 2 studies
[38]
[39], with fluoxetine in 2 studies [62]
[66], and with imipramine in one study [60]. Another study compared outcome of patients who received combination of fluoxetine
with saffron or placebo [18].
Table 1 Characteristics of clinical trials of antidepressant effect of saffron and their
results.
|
Type of study
|
population
|
Sample size
|
scale
|
Type of administration compounds
|
Compared with
|
Duration
|
Results
|
Author (Year) (reference)
|
|
Pilot DBRCT
|
Adult outpatients with mild to moderate depression
|
40
|
17-item HAM-D.
|
petal of C. sativus 15 mg bid
|
Fluoxetine 10 mg bid
|
8 weeks
|
effective similar to fluoxetine
(F=0.03, d.f.=1, P=0.84)
|
Akhondzadeh (2007) [66]
|
|
placebo-controlled DBRCT
|
adult outpatients with mild to moderate depression
|
40
|
17-item HAM-D.
|
capsule of petal of C. sativus 30 mg/day (BD)
|
placebo
|
6 weeks
|
a significantly better outcome than placebo
(d.f.=1, F=16.87, p<0.001)
|
Moshiri (2006) [39]
|
|
single-centre placebo-controlled DBRCT
|
adult outpatients with mild to moderate depression
|
40
|
17-item HAM-D.
|
capsule of saffron 30 mg[sol]day (BD)
|
placebo
|
6 weeks
|
a significantly better outcome than placebo
(d.f.=1, F=18.89, p<0.001)
|
Akhondzadeh, (2005) [38]
|
|
DBRCT
|
adult outpatients with mild to moderate depression
|
40
|
17-item HAM-D.
|
(hydro-alcoholic extract) saffron 30 mg/day (BD)
|
Fluoxetine 20 mg/day (BD)
|
6 weeks
|
effective similar to fluoxetine
(F=0.13, d.f.=1, P=0.71)
|
Noorbala (2005) [62]
|
|
single-center DBRCT
|
adult outpatients with mild to moderate depression
|
30
|
17-item HAM-D.
|
capsule of saffron 30 mg/day (TDS)
|
capsule of imipramine 100 mg/day (TDS)
|
6 weeks
|
to be effective similar to imipramine
(F=2.91, d.f.=1, P=0.09)
|
Akhondzadeh, (2004) [60]
|
|
placebo-controlled DBRCT
|
women (20–45 y) with regular menstrual cycles and PMS at least 6 months
|
50
|
17-item HAM-D. & checklist of 17 premenstrual daily symptoms
|
capsule saffron 30 mg/day (15 mg twice a day
|
placebo
|
For a 2 menstrual cycles
|
effective in relieving symptoms of PMS
|
Agha-Hosseini (2008) [69]
|
|
double-blinded
|
medical students
|
50
|
BDI scale
|
drank tea contained-
saffron in 3 times in day
|
Pre-test Post-test
|
4 weeks
|
decreasing of The mean score
(P<0.0001)
|
Masinaei Nezhad, (2005) [70]
|
|
DBRCT
|
adult patients who completed a questionnaire (BDI)
|
70
|
BDI scale
|
capsule of saffron 100 mg/day
|
placebo
|
12 weeks
|
the BDI score in saffron group decreased about 2 times than that of placebo group
|
Shemshian, (2011) [71]
|
DBRCT=double-blind, randomized clinical trial, HAM-D=Hamilton Depression Rating Scale,
BDI= Beck Depression Inventor
Researchers have attempted to perform clinical trials on most typical antidepressants
with the inclusion criteria, such as age ranges (18–65 years old) and frequency of
genders, and exclusion criteria, e. g. co-morbidity of psychiatric illness, specific
types of personality disorders etc. [67]. Participants were outpatients who met the DSM- IV criteria for major depression
(mild to moderate depression).
Sample size were equal (n=30–40) in all studies, although some of the reviewers stated
that their sample sizes were not enough [68]. All of these studies were performed on similar population. Because of the effect
of various social factors on depression, a multicenter clinical trial seemed to be
more of use.
Antidepressant effect of saffron was evaluated by the Hamilton Depression Rating Scale
(HAM-D). It is shown that saffron could decrease HAM-D about 10–14%, generally considered
as remission ([Table 1]) [67].
Based on clinical trial guidelines, a minimum of 4–6 weeks appear to be an appropriate
duration [67] which has been observed by all of them; although, this could not reflect the preventive
effect of saffron on exacerbation of depression and needs to be evaluated in extended
studies.
In 2 studies [38]
[39] which compared saffron with placebo, authors reported no significant differences
between the 2 groups in terms of observed side effects. Nevertheless, it seems that
the total number of reported adverse effect by patients in saffron group were more
than that of control (29 vs. 13 and 17 vs. 10). The most frequent adverse effect of
saffron which had been reported in all trial was anxiety ([Table 2]) followed by an increase or a decrease in the appetites, nausea and headache. None
of these studies had any report about past medical history of their participants.
This is not entirely obvious whether they were treated with other medications before
being included in the study. Furthermore, the authors did not completely defined whether
patients were treated with other psychological treatments, such as psychotherapy or
family therapy.
Table 2 The frequency of saffron’s adverse effects through clinical trials on depression.
Number (percent). Total number of cases are 129 patients.
|
Author [year] (reference)
|
Mansoori P [2011][20]
|
Akhondzadeh Basti [2007] [66]
|
Akhondzadeh S [2004] [60]
|
Akhondzadeh S [2005] [38]
|
Moshir E [2006] [39]
|
Noorbala A [2005] [62]
|
Agha-Hosseini [2008] [69]
|
Total
|
|
Compare with
|
placebo
|
fluoxetine
|
imipramine
|
placebo
|
placebo
|
fluoxetine
|
placebo
|
|
|
Anxiety
|
2 (20)
|
4 (20)
|
4 (26.7)
|
3 (15)
|
4 (20)
|
3 (15)
|
|
20 (16)
|
|
Decreased appetite
|
|
5 (25)
|
2 (13.3)
|
2 (10)
|
4 (20)
|
2 (10)
|
3 (12.5)
|
18 (14)
|
|
Increased appetite
|
|
1 (5)
|
1 (6.7)
|
5 (25)
|
|
5 (25)
|
4 (16.7)
|
16 (12)
|
|
Nausea
|
|
3 (15)
|
2 (13.3)
|
2 (10)
|
5 (25)
|
2 (10)
|
2 (8.3)
|
16 (12)
|
|
Headache
|
|
2 (10)
|
3 (20)
|
3 (15)
|
3 (15)
|
3 (15)
|
3 (12.5)
|
17 (13)
|
|
Heart pounding
|
|
3 (15)
|
|
|
4 (20)
|
|
|
7 (5)
|
|
Hypomania
|
|
|
2 (13.3)
|
2 (10)
|
|
|
2 (8.3)
|
6 (5)
|
|
Tremor
|
|
2 (10)
|
|
|
3 (15)
|
|
|
5 (5)
|
|
Dry mouth
|
3 (30)
|
|
1 (6.6)
|
|
|
|
|
4 (3)
|
|
Sweating
|
|
2 (10)
|
|
|
2 (10)
|
|
|
4 (3)
|
|
Stomach pain
|
|
|
|
|
4 (20)
|
|
|
4 (3)
|
|
Constipation
|
1 (10)
|
|
2 (13.3)
|
|
|
|
|
3 (2)
|
|
Sexual dysfunction
|
|
3 (15)
|
|
|
|
|
|
3 (2)
|
|
Restlessness
|
2 (20)
|
|
|
|
|
|
|
2 (2)
|
|
Insomnia
|
|
2 (10)
|
|
|
|
|
|
2 (2)
|
|
Daily drowsiness
|
1 (10)
|
|
|
|
|
|
|
1 (1)
|
|
Morning drowsiness
|
1 (10)
|
|
|
|
|
|
|
1 (1)
|
|
Sedation
|
|
|
|
1 (5)
|
|
1 (5)
|
1 (4.2)
|
3 (2)
|
|
Urinary retention
|
|
|
1 (6.7)
|
|
|
|
|
1 (1)
|
|
Total
|
10
|
27
|
20
|
18
|
29
|
16
|
15
|
133
|
Through our review of the literatures, we found another clinical trial on the effect
of saffron on premenstrual syndrome [69]. The researchers had used 17-item HAM-D scoring for evaluating the outcome. They
showed that administration of 30 mg/day (15 mg twice a day) saffron capsules for 2
menstrual cycles could reduce the depression score as well as the menstruation symptoms
([Table 1]) in comparison to placebo. The most reported adverse effect of saffron on this study
was a change in appetite ([Table 2]).
We also found 2 other abstracts of clinical trial on antidepressant effect of saffron
that were presented in congresses as poster presentation. They had evaluated the antidepressant
effect of saffron by BECK depression score [70]
[71]. One abstract had studied effect of drinking a saffron- containing tea for 4 weeks
in medical students. It was revealed that saffron could reduce depression score [70]. The aim of the other study was to evaluate the effect of 100 mg/day saffron vs.
placebo in 70 patients for 12 weeks [71], also reporting the effectiveness of saffron. However, these 2 studies had a bigger
sample sizes (n=50 and 70) and a longer treatment duration (4 and 12 weeks) than the
previous studies. Since the abstracts were only published, we could not assess the
studies thoroughly.
It seems that now is the time for evaluating antidepressant effect of saffron by multicenter,
crossover, and large scale as third phase of clinical trials.
Physical fatigue
Production of reactive oxygen species and free radicals, which are responsible for
exercise-induced protein oxidation and contributes to physical fatigue, is promoted
during muscular exercise [72]
[73]. Administration of crocetin as an antioxidant [56]
[74] may attenuate physical fatigue. Mizuma and colleagues evaluated efficacy of 15 mg
of crocetin in a double-blind, placebo-controlled, 3-way crossover study on physical
fatigue in 14 Japanese healthy volunteers (7 men and 7 women) for 8 days [75]. They administrated crocetin (15 mg/day), ascorbic acid (3 000 mg), or placebo capsules
for 1 week before the experimental procedure. They found that men, who received crocetin
alone, had significantly higher change in maximum velocity from 30- to 210-min. They
could not find such difference in women [75]. The authors related their finding to antioxidant and alveolar oxygen transport
augmentation properties of crocetin. However, they had not measured and reported any
oxidant or antioxidant biomarkers or criteria of oxygenation.
Endocrinology and Gynecology
Endocrinology and Gynecology
Erection dysfunction (ED) and infertility
Recently, different herbal remedies have been assessed as effective treatments for
male infertility and other male sexual dysfunctions. Saffron has been known for centuries
to have aphrodisiac properties. Moreover, the aphrodisiac activities of saffron aqueous
extract and its constituent crocin, in male rats have been previously declared [76].
In a pilot clinical study on 20 men with erectile dysfunction, patients were observed
for 10 days taking 200 mg tablets of saffron every morning. The results showed a statistically
significant improvement in both tip and base rigidity and tumescence. Moreover, saffron
was considered positively effective on sexual function of patients with erectile dysfunction
even after a short-time treatment [77]. However, this was a pilot study and the sample number was rather few. Additionally,
there were no control group and no placebo was utilized.
In a similar study to assess the efficacy and safety of saffron in erectile dysfunction,
after 4 weeks of baseline evaluation, 346 men with erectile dysfunction received Sildenafil
or saffron (30 mg BID) for 12 weeks. No significant improvements were observed in
the international index of erectile function domains, Sexual Encounter Profile questions
and Erectile Dysfunction Inventory of Treatment Satisfaction questionnaire scores
with saffron administration. The authors reported that their findings did not support
beneficial effects of saffron administration in men with erectile dysfunction [78]. This might be attributed to the low dose of saffron (30 mg BID) prescribed in comparison
to the previous study.
On the other hand, Safarinejad et. al studied the effect of saffron vs. placebo on
idiopathic male factor infertility on 260 infertile men with idiopathic oligo-asthenoteratozoospermia
(OAT). Patients received either 60 mg/day saffron or placebo for 26 weeks. Afterwards,
the 2 groups were compared with each other regarding changes in semen parameters and
total seminal plasma antioxidant capacity. The results of the study showed saffron
did not improve semen parameters in infertile men with idiopathic OAT [79].
In a case-report a 25-year-old woman with a 2-year primary infertility who was diagnosed
with unilateral tubal blockage, received Unani herbal Majoon, one of its ingredients
being C. sativus, for 2 successive cycles. The outcome was the patient’s pregnancy 2 months after
therapy. C. sativus L. was reported to recover infertility due to crocetin and flavonoids contents. [80]. Nevertheless, it cannot be directly concluded whether or not the positive result
was due to saffron.
Premenstrual syndrome (PMS)
The effect of saffron has been studied on some gynecologic disorders, mostly on premenstrual
syndrome (PMS). PMS is a group of cyclical and recurrent emotional, physical, psychological,
and mood discomfort that typically occurs after ovulation and before the onset of
menstrual period [81].
A RDBPCCT study investigated the effect of stigma of saffron on relieving the symptoms
of this syndrome on 20–45 aged women with; regular menstrual cycles and the experience
of the symptoms of PMS for at least 6 months.They received either 30 mg per day saffron
or placebo. PMS symptoms were evaluated using a Premenstrual Daily Symptoms (PDS)
questionnaire and Hamilton Depression Rating Scale (HAM-D). There was a significant
difference in the efficacy of saffron in the Total PDS and HAM-D. The results indicated
the positive effect of C. sativus L. in alleviation of PMS symptoms [69].
Primary dysmenorrhea
Primary dysmenorrhea, with a prevalence rate of approximately 90%, is described as
cramping pains in the lower abdomen before or throughout the menstruation period without
the presence of other diseases [82]. The effect of saffron has been assessed in the treatment of primary dysmenorrhea
using a pilot RDBPCCT on 180 female students aged 18–27 years old suffering from primary
dysmenorrhea. Individuals were randomly divided into 3 groups taking either herbal
drugs (saffron, celery seed, and anise extracts 3 times a day for 3 days) or mefenamic
acid or placebo, starting from the onset of bleeding or pain. Severity and duration
of pain were evaluated for 3 months. Both herbal and chemical drugs efficiently comforted
the menstrual pain in comparison with the placebo [83]. However, since the herbal drug contained 3 herbs, this effect cannot be attributed
to a specific herb.
Another study attempted to elucidate the effects of saffron odor on some gynecologic
symptoms including PMS, dysmenorrhea and irregular menstruation. 35 women with normal
olfactory ability and normal menstrual cycles were exposed to saffron odor for 20 min.
Saliva samples were subsequently analyzed for cortisol, testosterone and 17-beta estradiol
concentrations utilizing enzyme immunoassay method. The State-Trait Anxiety Inventory
(STAI) was used for psychological testing. The outcome was a considerable decline
in cortisol levels and an increase in estradiol levels after exposure to saffron odor
in both follicular and luteal phases. Moreover, the STAI score decreased in the follicular
and luteal phases in the saffron group. Therefore, the findings of this RDBPCCT suggested
positive physiological and psychological effects of saffron odor in management of
PMS, dysmenorrhea and irregular menstruation [84]. However, in this study the fragrance of saffron was diluted in ethanol to be smelled
by the test individuals, a fact that implies that such solvent may be considered an
effective treatment.
Snacking and appetites
Snacking and compulsive eating are disturbed dietary behaviors which are consequence
of mood disorders. Stress-induced eating accompanied with a preference for high-sugar
and high-fat food consumption, is powerful reinforcing of snacking [85]. Several studies have shown mood elevation and anti-anxiety properties of saffron
[39]
[61]
[65]
[66]. Gout et al. evaluated the effect of saffron on reducing the snacking frequency
and demand, in 60 healthy, mildly overweight women, during a RDBPCCT [40]. They administrated 176.5 mg extract of saffron or placebo per day over an 8-week
period and recorded body weight changes and snacking frequency. They found that saffron
caused a significantly greater body weight reduction than the placebo after 8 weeks,
and a significant decrease in snacking frequency after 4 weeks. However, other anthropometric
dimensions and vital signs did not not change between the saffron and placebo groups
[40]. They reported no major adverse effects as well. Therefore, they have offered saffron
as an adjuvant supplement for people involved in weight loss programs whose weight
gain is particularly due to stress or depression [40].
Immunology and Allergy
Feo et al. have studied the sensitization to saffron and its clinical significance
as an occupational allergen [86]. In their study, 2 groups of subjects were included: one group was exposed to saffron
in an important saffron area of Spain as workers (picking, manual extraction of stigmas,
and roasting the stigmas of saffron), and the other group comprised of 237 unexposed
patients with a positive history of allergy. Individuals having positive Skin Prick
test afterward went through Radioallergosorbent test (RAST) to evaluate the cutaneous
and specific antibody responses. Saffron allergens from pollen and stamens were then
characterized by SDS-PAGE immunoblotting. No allergens were verified in pistils [86].
In another study directed in Iran, more than 200 saffron workers referring to an allergy
clinic were evaluated regarding the clinical symptoms and Prick test. Results illustrated
that saffron, and in particular its pollen, was an inhalation allergen and female
workers were more sensitive to this plant than the male ones [87].
The effects of 100 mg saffron tablets taken daily for 6 weeks, were evaluated on 45
healthy middle-aged men through a RDBPCCT [88]. Different hematological and immunological parameters were assessed 3 weeks after
treatment. Saffron increased IgG levels while decreasing IgM levels in comparison
with the baseline and the placebo. Moreover, it could decrease the percentage of basophils
and also the platelets count, but it increased the percentage of monocytes. The results
of this study suggested that a sub-chronic daily dose of 100 mg saffron had short-term
immunomodulatory effects with no side effects [88].
Skin
As one of the Persian traditional medications, saffron, has been used in order to
add shine, lighten the skin and reduce dark pigments, dark circles under the eyes,
acne and pimple [89]. It is suspected that crocin inhibits active compound of DNA damage, or acts as
an activator for DNA excision repair enzymes [90]. Furthermore, saffron has antisolar effect and can absorb UV rays of sun [91].
Vyas et al. used 3% dry extract of saffron being inoculated in o/w cream, lotion and
face powder formulations and tested it by patch test on individuals in age groups
of 18–28. They reported that saffron could clearly enlighten the skin. They suggested
these effects are due to crocin and crocetin presented in saffron [92]. The shining and depigmentation effects of saffron may be attributable to antioxidant
effect of crocin and crocetin [17]
[93]. However, Vyas had no appropriate methodological clinical trial criteria such as
number of groups, control group and the human method. We could not find any other
article about the effect of saffron on skin.
Saffron has been used as an ingredient in anti-itching creams possessing emollient
and antipruritic effects in a unicentric, open label randomized controlled study [94]. For the case group, a topical polyherbal formulation cream containing extracts
of turmeric 16% (Curcuma longa), saffron 0.025% (C. sativus), sandalwood 8% (Santalum album), vetiver 0.5% (Veteveria zizanioides), lata kasturi 0.1% (Abelmoschus moschatus), mehendi 3% (Lawsonia inermis), tulasi 3% (Ocimum sanctum), yastimadhu 0.5% (Glycyrrhiza glabra), turmeric oil 0.1%, surasar 0.5%, and swarna bhasma 0.00032% in a nongreasy cream
base was used. They applied standard antipuritic cream containing urea, lactic acid,
propylene glycol and light liquid paraffin. They reported that this application could
reduce both pruritus and composite scores in case group as well as in the control
standard group. Adverse events like mild local skin irritation and burning sensation
at the site of application were reported in only 3 out of 25 cases, being as frequent
as in the control group [94]. However, this is the only clinical trial on antipuritic effect of saffron and the
results are not utterly related to saffron.
Conclusion
Saffron and its constituents are shown to possess multiple useful effects on several
diseases such as Alzheimer and depression as well as in gynecology disorders. Due
to high safety level of this phytomedicine, it can be applied in clinical trials for
majority of its effects. Some applications of saffron such as antidepressant and anti-Alzheimer
properties are sufficient for the subsequent phase of clinical trials or drug developments.
However, most of others effects and applications of saffron require further clinical
and animal studies.
