Cardiovasc Toxicol
DOI 10.1007/s12012-012-9181-z
Cardiovascular Benefits of Black Cumin (Nigella sativa)
Adel Shabana • Ayman El-Menyar •
Mohammad Asim • Hiba Al-Azzeh •
Hassan Al Thani
Ó Springer Science+Business Media, LLC 2012
Abstract Black Cumin (Nigella sativa), which belongs to
the botanical family of Ranunculaceae, commonly grows
in Eastern Europe, the Middle East, and Western Asia. Its
ripe fruit contains tiny black seeds, known as ‘‘Al-Habba
Al-Sauda’’ and ‘‘Al-Habba Al-Barakah’’ in Arabic and
black seed or black cumin in English. Seeds of Nigella
sativa are frequently used in folk medicine in the Middle
East and some Asian countries for the promotion of good
health and the treatment of many ailments. However, data
for the cardiovascular benefits of black cumin are not well-
established. We reviewed the literature from 1960 to March
2012 by using the following key words: ‘‘Nigella sativa,’’
‘‘black seeds,’’ and ‘‘thymoquinone.’’ Herein, we discussed
the most relevant articles to find out the role of Nigella
sativa in the cardiovascular diseases spectrum especially
when there is a paucity of information and need of further
A. Shabana
Deparment of Cardiology, Hamad Medical Corporation, Doha,
Qatar
A. Shabana
A. El-Menyar (&)
Department of Clinical Medicine, Weill Cornell Medical School,
PO Box 24144, Doha, Qatar
e-mail: aymanco65@yahoo.com
A. El-Menyar
M. Asim
Clinical Research, Trauma section, Hamad Medical Corporation,
Hamad General Hospital, PO Box 3050, Doha, Qatar
H. Al-Azzeh
Al-Ghad Technology for Food Additives [MVM(Path)],
Amman, Jordan
H. Al Thani
Department of Vascular Surgery, Hamad Medical Corporation,
Doha, Qatar
studies in human to establish the utility of Nigella sativa in
cardiovascular system protection.
Keywords Nigella sativa
Black seeds
Thymoquinone

Cardiovascular
Cumin
Introduction
Complementary and alternative medicine has become
popular worldwide over the past 20 years [1]. The seeds of
Black cumin (Nigella sativa) were among the accompa-
nying articles found in the tomb of Egyptian Pharaoh
Tutankhamen [2]. Thus, Nigella sativa (NS) probably had
an important role in the practices of the ancient Egyptians
[3], who described it as a panacea (cure for problems and
diseases). The historical references to these seeds are also
present in some of the oldest religious and medical texts.
For example, Hippocrates and Dioscorides referred them as
‘‘Melanthion’’ and were identified and described by Lin-
naeus in 1753 [4]. The Bible describes black seed as the
‘‘curative black cumin’’ (Isaiah 28:25, 27 NKJV) [4]. Seeds
of NS are the common drug used in islamic prophet’s
medicine, since prophet Muhammad (PBUH) stated that it
is the remedy for every disease except death (Sahih Buk-
hari 7:591) [5]. It is stated that he himself [PBUH] used to
take these seeds with honey syrup for therapeutic purpose
[6]. Ibni Sina, known in the West as Avicenna, also
referred NS as the seed ‘‘that stimulates the body’s energy
and helps recovery from fatigue’’ in his great book ‘‘The
Canon of Medicine’’ [7].
NS is widely used as a medicinal herb, not to be mis-
taken with common cumin seed (Cuminum cyminum) that
belong to the botanical family Umbelliferae [4]. NS is a
spice that grows in the Middle Eastern region and in

Western Asian countries including India, Pakistan, and
Afghanistan. It is known by different names. For example,
in Arabic it is termed as ‘‘Habbah Sawda’’ [black seed] or
‘‘Habbat el Baraka’’ (Seeds of blessing). In India, it is
called ‘‘Kalonji,’’ while in China it is known as ‘‘Hak Jung
Chou’’ [8]. The plant belongs to the Ranunculaceae family
of flowering plants, including multiple species, among
which NS is the most extensively investigated for thera-
peutic purposes [8]. Figure 1 shows NS plant, flowers, and
seeds.
During the last two decades, most of the studies dealt
with the volatile oil of the seeds and its major constituents
(i.e., the two purified components of NS seed, thymoqui-
none and dithymoquinone). These studies revealed a mul-
tirange of actions that covered almost all known diseases of
the human body systems [9].
Traditional Uses
Traditionally, the seeds and oil were used in several diseases.
The seeds are used as a pungent, carminative, emmenagogue,
galactagogue, aromatic, stimulant, appetizer, diuretic, anthel-
mintic, digestive, febrifuge, expectorant, abortifacient, and
Fig. 1 Nigella sativa whole plant, flower, and seeds
Cardiovasc Toxicol
diaphoretic. They were also used in ascites, cough, jaundice,
fever, piles, anorexia, dyspepsia, flatulence, dysentery,
diarrhea, and amenorrhea and in the treatment of worms and
skin eruptions [4, 9, 10].
Commonly, the seeds were used as a spice and food
preservative. In folk medicinal practices, they are ingested
with food or mixed with honey [4]. Several beneficial
pharmacological effects have been attributed to various
crude or purified components of these seeds including
antihistaminic, antihypertensive, hypoglycemic, antifungal,
anti-inflammatory, and immunity booster along with sig-
nificant antineoplastic activities [11–16]. These studies
collectively provide early indication that further develop-
ment of agents derived from NS seeds could be useful in
modern medicine [4].
The Chemical Composition of the Seeds and Oil
The chemical composition of the NS seed is diverse and
contains amino acids, carbohydrates, fixed and volatile oils,
alkaloids, saponins, and many other compounds [4, 9, 17].
The chemical analysis of NS total oil showed the presence
of both fixed and volatile oil. The major component was
Cardiovasc Toxicol
the fixed oil, whereas the volatile oil ranged from 0.4 to
0.7 % of the seeds’ weight. The chemical composition of
black seed fixed oil includes mixture of oils such as lino-
leic, oleic, linolenic, arachidic, palmitoleic, eicosadienoic,
palmitic, stearic and myristic acid [9, 18].
Specific chemical analyses of the volatile oil started
around 50 years ago and were complemented by most
recent reports, using different chromatography techniques
for separating components of the oil samples. They showed
the presence of many components, including thymoqui-
none [the major active principle of NS and constitutes
about 30 % of its volatile oil or ether extract], carvacrol,
tanethole, and 4-terpineol, and all of them have demon-
strated respectable radical scavenging activity. The oil
samples showed variable antioxidant activity that was
attributed mainly to the variable composition of these
constituents [4, 19–21].
Since last four decades, various researchers have
investigated the pharmacological actions of the whole
seeds of NS (crushed powder or an extract) worldwide. The
aqueous, ethanolic, methanolic, petroleum ether, hexane,
and ethereal extracts were studied mainly in animals, and
to a lesser extent in humans. The most widely studied
component of black seed is the volatile oil and its con-
stituent thymoquinone [9, 17].
Cardiovascular Effects of NS
The Effect of NS on Diabetes Mellitus and Metabolic
Syndrome
The hypoglycemic and antidiabetic effects of NS have been
reported in several in vitro and in vivo studies (animal
studies) but few have been performed on humans [22–24].
Both pancreatic and extra-pancreatic mechanisms have
been proposed for such effects.
Animal models for type I diabetes have been mainly
induced by streptozotocin injection (with or without nico-
tinamide) or by cadmium treatment. The mechanisms
underlying the hypoglycemic effect of NS and its compo-
nents have been suggested to be mainly due to the pres-
ervation of beta cell integrity in the islets of Langerhans
with partial regeneration/proliferation of beta cells leading
to increased insulin levels [25–28]. However, in other
studies, the hypoglycemic effects were not paralleled by
stimulation of insulin release, suggesting extra-pancreatic
actions of NS [29]. This was also supported by evidence of
a decrease in hepatic gluconeogenesis in another study
[30]. In addition to hypoglycemic effects, NS oil and thy-
moquinone have been found beneficial in correcting
experimental diabetic neuropathy, which makes it a pos-
sible potential therapeutic agent for neuropathy [31, 32].
The benefit of NS has been validated in type II diabetes
in animal models as well as human subjects. Multiple
molecular targets and several mechanisms of action have
been suggested to explain such benefit. In animal studies,
NS was found to inhibit intestinal glucose absorption in
vitro and in vivo, stimulate insulin release from pancreatic
islets, and exert an insulin-sensitizing actions in skeletal
muscles, adipocytes, and liver cells through the activation
of AMPK (adenosine monophosphate-activated protein
kinase) pathway, as well as PPARc (peroxisome prolifer-
ator-activated receptor gamma), and increasing muscle
GLUT4 (glucose transporter 4) content [24, 33–36].
Few human studies have been published in the literature
assessing the effect of NS on glycemic control in patients
with type II diabetes mellitus as well as patients with
insulin resistance syndrome [23, 37]. Bamosa and
coworkers administrated NS seeds to diabetic patients for
3 months and assessed their glycemic control. They found
that NS in a dose of 2 g/day could be a beneficial adjuvant
to oral hypoglycemic agents in these patients [23]. Qidwai
et al. [38] have also found favorable effect of NS seeds on
blood sugar and serum lipids in adults, but results were not
statistically significant.
Najmi et al. carried out a prospective study on 60 met-
abolic syndrome patients. The patients were divided into
two groups of 30 each. All patients were advised fixed
doses of statin and metformin tablets for a period of
6 weeks. In the second group, NS oil of 2.5 ml twice daily
was added for a period of 6 weeks. Fasting and postpran-
dial blood glucose, fasting lipid profile, and waist cir-
cumference were recorded before the therapy and after the
completion of the therapy. The results showed that the
second group had significant improvement in levels of
fasting blood sugar as well as total cholesterol and low-
density lipoprotein cholesterol (LDL-C). In summary, NS
therapy may prove to be promising in the prevention and
treatment of the insulin resistance syndrome [37].
Effect of NS on Lipid Profile
Several studies have reported favorable effects of NS on
lipid profile.
In cholesterol-fed animals, thymoquinone significantly
induced a reduction in total cholesterol, LDL-C, triglyc-
eride [TG], and thiobarbituric acid-reactive substances’
concentrations, with increase in high-density lipoprotein
cholesterol [HDL-C] levels [39]. Similar findings were
observed using NS powder and oil in other studies [35,
40–42]. Zaoui et al. [42] found that oral treatment with NS
oil decreased serum cholesterol and TG levels in normal
rats by 15.5 and 22 %, respectively.
Also, oral administration of powdered black seeds to
hypercholesterolemic patients at the dose of one gram daily

for 2 months significantly reduced the total cholesterol,
TG, and LDL-C levels and increased the HDL-C level [43].
Bamosa et al. [44] reported decreased levels of glucose
and cholesterol in healthcare professionals treated with 2
gram of NS capsules twice daily. In a recent study by
Tasawar et al. 8 subjects were divided into two groups
through random stratification. One group was given NS and
statin, while the second group was given only statin daily.
Fasting blood samples were taken before and after 2 and
6 month’s treatment. In the first group, total cholesterol,
LDL-C, and triglycerides decreased significantly after the
treatment by 14.58, 23, and 15.16 %, respectively. Also,
there was significant increase in HDL-C (by 3.18 %) after
6 months, compared to the second group. This study
showed that NS is helpful in normalization of the lipid
profile and in turn prevents cardiovascular disorders [45].
Moreover, Dehkordi and Kamkhah [46] observed a
significant reduction in serum total cholesterol and LDL-C
in patients with mild hypertension after 8 weeks of black
seed extract oral administration.
The hypolipidemic effect of NS does not seem to be due
to one component only, but rather to the synergistic action
of its different components, including thymoquinone,
sterols, flavonoids, and the high content of polyunsaturated
fatty acids [17]. Several mechanisms have been postulated
to explain this hypolipidemic effect, which includes inhi-
bition of de novo cholesterol synthesis or stimulates bile
Fig. 2 The antiatherogenic potential of Nigella sativa seeds and oil (modified from ref. [40]: Al-Naqeep et al.: (2011) Evidence-Based
Complementary and Alternative Medicine), Hindawi publishing Corporation
Cardiovasc Toxicol
acid excretion. It is well known that both actions reduce
serum cholesterol levels [44, 47]. Another mechanism
depends on NS antioxidant role affecting nonenzymatic
lipid peroxidation [22, 48].
Antiatherogenic Effects of NS
Al-Naqeep et al. studied the effect of black seeds powder
and oil on atherosclerosis in diet-induced hypercholester-
olemic rabbits in comparison with statin. Figure 2 shows
the antiatherogenic potential of NS seed as well as oil in
rabbits. The investigators broadly divided the study animals
into two groups: the first group with normal diet and the
second group with cholesterol-supplemented diet. The
second group was further subdivided into three groups, that
is, (a) no treatment, (b) administration of NS seed/oil, and
(c) administration of hypocholesterolemic agent (simva-
statin). They found that feeding rabbits with NS either
(powder or oil) significantly improve lipid profile after 2, 4,
6, and 8 weeks compared with the control group. Exami-
nation of aortic intima at the end of the 8th week showed
significant inhibition of plaque formation. Furthermore, the
intima : media ratio was significantly decreased in the NS
supplemented groups compared with the control group [40].
Nader and colleagues, in another study, found similar
beneficial effects of thymoquinone on lipid profile of
cholesterol-fed rabbits, with histopathological evidence of
Cardiovasc Toxicol
protection against hypercholesterolemia-induced aortic
tissue damage [39].
In addition to its beneficial actions on atherosclerosis
(through modulating major risk factors as diabetes melli-
tus and dyslipidemia), NS has been investigated for its
effect on the progression of monocyte-derived macro-
phage growth [49]. Such macrophages have been shown to
uptake oxidized LDL, becoming foam cells in the blood
vessel wall, accelerating the local inflammatory response
that eventually leads to atherosclerotic plaque formation
[50]. Mat et al. isolated primary human monocytes from
whole blood and treated them with NS oil. The finding of
this study provided preliminary support on regulation of
cell growth and differentiation in monocyte and mono-
cyte-derived macrophages by NS oil. NS was found to
exert its effects via decreasing the productions of pro-
inflammatory mediators secreted by primary macrophage
[49].
Effect of NS on Endothelial Dysfunction
Endothelial dysfunction is a pathological condition that
contributes to the pathogenesis of several cardiovascular
diseases and has been found in patients with dyslipidemia,
hypertension, diabetes mellitus, obesity, atherosclerosis,
and aging as well. All such conditions are associated with
overproduction of reactive oxygen species in the arterial
vessel wall [51, 52]. A recent data, mainly targeting aging-
related endothelial dysfunction, demonstrated that thymo-
quinone improved endothelial function at least in part,
through inhibition of oxidative stress and normalization of
the angiotensin system [52].
Antiplatelet Effects of NS
The methanol-soluble portion of oil prepared by com-
pressing NS seeds has been used by Enomoto et al. and
discovered to have strong inhibitory effects on arachidonic
acid-induced platelet aggregation. Some isolated com-
pounds from the oil had stronger potency than aspirin [53].
Effect of NS on Heart Rate and Blood Pressure
Controversial findings have been reported regarding car-
diovascular actions of NS or its active ingredients. Some
studies reported no effect on blood pressure levels in ani-
mals or humans, whereas others showed a dose-dependent
decrease in the arterial blood pressure and heart rate in
normal or spontaneously hypertensive rats [12, 54, 55].
El-Tahir et al. [55] suggested that such cardiovascular
depressant effects were mediated mainly centrally via
indirect and direct mechanisms that involved both
5-hydroxytryptaminergic and muscarinic mechanisms.
NS was also effective in decreasing the elevated heart
rate in cadmium-treated rats [26]. Khattab and Nagi [56]
studied the effects of thymoquinone in rats after chronic
inhibition of nitric oxide synthesis with N[omega]-nitro-
L-arginine methyl esters [L-NAME] and concluded that
thymoquinone is effective in protecting rats against
L-NAME-induced hypertension and renal damage, possibly
via antioxidant activity.
One of the few studies in the literature conducted on
humans showed that NS extract administration for
2 months to patients with mild hypertension reduced both
systolic and diastolic blood pressures in a dose-dependent
manner [46]. Favorable effects of the seeds on blood
pressure have also been reported in another human study
by Qidwai et al. [38].
Effect on Cardiac Mass and Contractility
El-Bahai et al. reported evidence of physiological
improvement and beneficial cardiac hypertrophy in rats
provoked by long-term NS supplementation. NS supple-
mentation induced moderate overall cardiac hypertrophy.
The isolated perfused hearts of NS-treated rats showed
enhanced levels of baseline peak tension [57]. Further-
more, the supplementation of NS demonstrated encourag-
ing resulted on intrinsic cardiac contractile properties
without evidence of increased cardiac work load or energy
consumption in vivo [58].
Other studies showed the effects of NS (aqueous and
macerated extracts) on heart rate and contractility of the
isolated heart in guinea pigs. The results showed a potent
inhibitory effect of both extracts on heart rate and con-
tractility that was comparable or even higher than that of
diltiazem. It may be either due to calcium channel inhibi-
tory action or an opening effect on potassium channels of
the isolated heart [59, 60].
Cardioprotective Effects of NS Against Chemical
Toxicity
Cyclosporine A is the most frequently used agent in
transplant surgery and in the treatment of autoimmune
diseases. However, the drug has multiple adverse effects
including hypertension, cardiotoxicity, and vascular endo-
thelial dysfunction [61, 62]. Ebru et al. [63] studied the
effects of NS oil on cyclosporine A-induced cardiomyop-
athy and showed that pretreatment with NS oil decreased
the subsequent cyclosporine A injury in rat heart, with
normalized cardiac histopathology, decreased lipid perox-
idation, improvement in antioxidant enzyme status and
cellular protein oxidation.
Cyclophosphamide is another chemotherapeutic agent
with known cardiotoxic effects. Nagi et al. examined the

possible protective effects of thymoquinone against
cyclophosphamide-induced cardiotoxicity in rats. Interest-
ingly, thymoquinone supplementation resulted in a com-
plete reversal of all the biochemical changes (in blood and
in heart tissues) induced by cyclophosphamide to their
normal values. Results of this study suggest that beneficial
effects of thymoquinone are attributed to its antioxidant
properties as well as its ability to improve the mitochon-
drial function and energy production in heart tissues [64].
Doxorubicin is a mainstay of cancer chemotherapy
despite its clinical limitations that arise from its cardio-
toxicity and the high incidence of multidrug resistance.
Recent studies revealed a protective effect of thymoqui-
none against doxorubicin-induced cardiotoxicity [65–67].
The superoxide scavenging and antilipid peroxidation may
explain such effect [67].
Cardioprotective Effect of NS Against
Hyperhomocysteinemia (HHcy)
HHcy is associated with higher risks of coronary, periph-
eral, and cerebral artery disease through the induction of a
pathogenic state of oxidative stress. El-Saleh et al. dem-
onstrated that under the state of induced HHcy in rats, there
were significant increases in the plasma levels of triglyc-
erides, lipid peroxidation, and cholesterol and in the
activities of glutathione peroxidase and superoxide dis-
mutase with a significant depression of the total antioxidant
status. All of these effects were almost totally blocked by
prior treatment with thymoquinone or black seed oil [68].
In summary, the beneficial effects of NS, either seeds or
its purified constituent, could be contributed to their cyto-
protective and antioxidant actions and to their effect on
some mediators of inflammation [17]. Table 1 shows the
experimental and clinical data for the effect of NS on the
cardiovascular system. Table 2 summarizes the mechanism
of actions of NS on the heart.
Main Noncardiac Pharmacological Activities of NS
Antioxidant Activity
Thymoquinone and NS seed extracts have been shown to
demonstrate antioxidant property through different mecha-
nisms in several recent reports [74, 75]. Thymoquinone
could act as a free radical and superoxide radical scavenger.
In addition, it preserves the activity of various antioxidant
enzymes such as catalase, glutathione peroxidase, and glu-
tathione-S-transferase [74]. It has been shown that thymo-
quinone could inhibit iron-dependent microsomal lipid
peroxidation successfully in rats with doxorubicin-induced
hyperlipidemic nephropathy [65, 76]. Sayed-Ahmed and
Cardiovasc Toxicol
Nagi have investigated the probable protective effects of
thymoquinone against gentamicin-induced nephrotoxicity.
Supplementation with thymoquinone resulted in significant
decline in reduced glutathione and increased levels of glu-
tathione peroxidase, catalase, and ATP. That study also
showed complete reversal of the gentamicin-induced
increased blood urea nitrogen, creatinine, thiobarbituric
acid-reactive substances, and total nitrate/nitrite to normal
range [77]. Both NS oil and thymoquinone can protect gastric
mucosa from acute alcohol-induced mucosal injury, which is
partly attributed to their free radical scavenging activity [78].
Furthermore, ethanolic extracts may protect against radia-
tion-induced oxidative damage in mice [79].
Hepatoprotective Activity
Thymoquinone and other NS seed extracts are also known
to have hepatoprotective activity in various settings.
In an animal study by Yildiz et al. NS treatment was
found to protect the rat liver against hepatic ischemia–
reperfusion injury. This may have clinical implications to
some hepatic surgeries and in hepatic transplantation where
ischemia reperfusion injuries are considered significant
problem [80].
Another recent animal study showed that NS adminis-
tration had protective effects on cholestatic liver injury in
rats. The authors suggested that the underlying mechanism
of action might involve attenuation of enhanced neutrophil
infiltration and oxidative stress in the liver tissue [81].
Furthermore, NS and components have been found to
protect the liver against the effects of several toxins,
including tert-butyl hydroperoxide, carbon tetrachloride,
aflatoxin B, and lead [82–85]. The attenuated liver damage
may be due to the decrease in pro-inflammatory cytokines
and T-cell proliferation as described by Michel et al. [86].
Finally, thymoquinone supplementation reduced liver
dysfunction induced by endotoxemia in rats, partly via anti-
apoptotic and antioxidant activities. This was proven through
both biochemical and pathological examination [87].
Anti-Inflammatory Activity
The NS oil and thymoquinone have been found to exhibit
potent anti-inflammatory effects on several inflammation-
based models through the suppression of prostaglandins
and leukotrienes [88]. Asthma and rheumatoid arthritis are
examples of chronic inflammatory disorders involving a
range of inflammatory mediators and different pathways
[4]. In a recent clinical trial, 29 asthmatic adults were
randomly divided into two groups; a control group and
treatment group with NS seed extract with a 3-month fol-
low-up. It was observed that asthma symptoms, frequency
of asthmatic attacks, and pulmonary function test values in
Table 1 Recent clinical and experimental studies for the effect of Nigella sativa on the cardiovascular system
References Type of Study population NS component used Results
study

Le et al. [35] In vivo Rats Petroleum ether extract of NS for 4 weeks There is a reduction in TG and increase in HDL
Najmi et al. [37] Human 60 pts with metabolic 2 gps; all given metformin and statin NS group shows significant improvement in TC, LDL, and fasting blood
Cardiovasc Toxicol

syndrome while NS oil added in one group for sugar

6 weeks
Qidwai et al. [38] Human 123 pts with dyslipidemia Powdered black seeds in capsules versus Black seeds have favorable effects on almost all lipid variables
placebo
Nader et al. [39] In vivo Cholesterol-fed rabbits Propolis or TQ Administration of TQ with cholesterol-enriched diet significantly reduced
TC, LDL-C, and TG, while that increased HDL-C concentration. Early
atherosclerotic changes were observed in high-cholesterol control group
that did not receive TQ
Al-Naqeeb et al. [40] In vivo Rabbits NS seed and oil NS significantly reduced TC and LDL-C and also enhanced HDL-C levels. In
addition, plaque formation was significantly inhibited while the
intima : media ratio was significantly reduced with NS
El-Dakhakhny et al. In vivo Rats Oral NS oil for 4 weeks There is a significant decrease in serum total cholesterol, LDL, and TG and
[41] increase in serum HDL
Zaoui et al. [42] In vivo Rats NS Oil for 12 weeks There is a significant decrease in TC and TG
Bhatti et al. [43] Human 10 pts with NS seed powder for two ms There is a significant reduction in TC, TG, and LDL and increase in HDL-C
hypercholesterolemia
Tasawar et al. [45] Human 80 pts with stable CAD Pts were 2 gps, (statin ? NS capsules] NS group had significant decrease in total cholesterol, LDL, and triglycerides
and (statin only) for 6 ms with significant increase in HDL-C levels compared with the other group.
Dehkordi and Human Pts with mild hypertension Oral NS seed extract supplement Daily use of NS seed extract for 2 months may have a blood pressure-
Kamkhah [46] lowering effect in patients with mild hypertension in addition to significant
decline in TC and LDL-C levels
Khattab and Nagi [56] In vivo NO deficient hypertensive TQ Treatment of rats with TQ decreased the elevated creatinine and increased
rats GSH to normal levels and attenuates hypertension and renal damage in NO
deficient hypertensive rats
El-Bahai et al. [57] In vivo Rats NS oral supplementation (2 months) There is enhanced levels of baseline peak tension, heart rate, and myocardial
flow rate, with significant increase in the tension developed per gram of left
ventricular weight
Al-Hariri et al. [58] In vivo Rats NS oral supplementation (2 ms) There is favorable results of NS supplementation on the intrinsic contractile
properties without evidence of an increased cardiac work load or energy
consumption
Boskabady et al. [59] In vitro Guinea pig hearts Aqueous and macerated extracts from NS Extracts from NS reduces heart rate and contractility that was comparable
and even higher than that of diltiazem.
Ebru et al. [63] In vivo Rats NS oil Pretreatment with NS oil reduced the subsequent cyclosporine A
cardiotoxicity, by normalized cardiac histopathology, decrease in lipid
peroxidation, improvement in antioxidant enzyme status and cellular
protein oxidation
 Cardiovasc Toxicol

LDL-C low-density lipoprotein cholesterol, TC total cholesterol, HDL-C high-density lipoprotein cholesterol, TG triglycerides, NS Nigella sativa, TQ thymoquinone, NO nitric oxide, pts
the treatment group significantly improved. Moreover, the

increased inotropic properties as well as maximal peak tension generation

TQ attenuates hypercholesterolemic atherosclerosis in addition to a decrease

TQ supplementation resulted in a complete reversal of all the biochemical

Significant decrease in serum LDL-C level and increase in serum HDL-C

Supplementation of oils was effective in reducing the abnormal values of

All doses produced significant reduction in TC, TG, LDL-C. and HDL-C
usage of the conventional medications in the treatment

changes (including creatine kinase and cholesterol levels) induced by

Short duration of NS administration caused moderate hypertrophy and

group decreased, while no changes were noticed in control
group [89].
NS has been found beneficial against rheumatoid

upon progressive cardiac stress by isoproterenol infusion

arthritis in both animal and human studies [90, 91].

cardiac and liver enzymes caused by oxidative stress

Antioxytocic Activity
with no linear dose- or time-dependent effects.

Preliminary reports have suggested that NS oil exhibits a

reversible inhibition of uterine smooth muscle contraction

in serum lipids and oxidative stress

induced by oxytocin stimulation in animals [11].

Immunomodulatory and Cytotoxic Activity

The oil and some of the active ingredients of black seed

cyclophosphamide

showed favorable immunomodulatory properties by aug-

menting the T cell and natural killer cell-mediated immune
responses [88]. The cytotoxic and immune-potentiating
effects of NS have been established in many in vivo and in
levels
Results

vitro studies [74].

The anticancer effects of thymoquinone are probably
Seeds in different doses and durations up

mediated through different mechanisms, which could be

broadly categorized into two modes of action: first, antipro-
liferation and induction of cell death and apoptosis [9, 92, 93],
and second, antimetastasis/antiangiogenesis action [94, 95].
NS fixed oil and essential oil

In addition, it was found to modulate various molecular tar-

gets, including p53, PTEN (phosphatase and tensin homolog),
NS component used

STAT3 (signal transducer and activator of transcription 3),

NS oral for 1 m

PPAR-c, activation of caspases, modulation of lipid peroxi-

to 14 days

dation, and generation of reactive oxygen species [74].

Other studies have also documented the specific effects of
NS oral

NS extracts, especially thymoquinone on multiple targets of

TQ

TQ

cancer cell lines [9, 94], suggesting that thymoquinone

deserves further extensive investigations for delineating its
role as an anticancer agent [4]. Thymoquinone significantly
decreased the proliferation of human breast, colon, pancreatic,
Study population

lung, and prostate cancer cells and also prevented their

metastasis without affecting normal cell proliferation [74, 96].
Similar effects have been found on acute lymphoblastic leu-
Rabbits

kemia cell lines [97]. Figure 3 shows the effect of thymo-

Rats

Rats

Rats

Rats

Rats

quinone on the lymphoid system in an experimental study.

The combination of thymoquinone or other NS compo-
nents with conventional chemotherapeutic drugs such as
Type of

In vivo

In vivo

In vivo

In vivo

In vivo

In vivo
study

cisplatin, ifosfamide, doxorubicin, gemcitabine, and oxa-

patients, gp group, ms months

liplatin could enhance the therapeutic effect as well as

reduces the chemotoxicity [66, 74, 98–101].
Table 1 continued

Ragheb et al. [72]

Sultan et al. [73]

Antimicrobial Activity
Dahri et al. [70]
Nagi et al. [64]

Yar et al. [71]

Ali et al. [69]
References

NS and its oil exhibited strong antimicrobial activity

against E. coli, Pseudomonas aeruginosa, and others
[102–104]. The ethanol extract of seeds has inhibited the
Cardiovasc Toxicol

Table 2 Summary of the

effects of Nigella sativa on the
heart
Direct effect Indirect effect
Inhibition of plaque formation Antidiabetic effect
Improves endothelial function Prevent and treat metabolic syndrome
Reduces intima/media ratio Reduction in total cholesterol, LDL,
and triglyceride
Inhibits arachidonic acid-induced Increases HDL
platelet aggregation
Reduces elevated heart rate Antioxidant effect
Reduces BP in hypertensive condition Protects against L-NAME-induced
hypertension and renal damage
Inhibitory effect on contractility
Cardioprotection against chemotherapy Protect against hyperhomocysteinemia effects

Fig. 3 The effect of thymoquinone on the lymphoid system in associated lymphoid tissue in the lung in thymoquinone-treated rats
animal. a Hyperplasia in the lymphoid follicle in the spleen white (Courtesy from Haba Al-Azzeh)
bulb in thymoquinone-treated rats. b Hyperplasia in the bronchial-

growth of methicillin-resistant Staphylococcus aureus
[105]. Thymoquinone was also found to prevent bacterial
biofilm formation against 11 human pathogenic bacteria
[106]. Similarly, antifungal activities of seeds and extracts
have been reported in several studies [107, 108].
Anthelmintic Activity
NS was shown to have an antiparasitic activity against
tapeworm and schistosomiasis in infected mice [109, 110].
Other Activities
Other reports include anticonvulsant, anxiolytic, antiuro-
lithiatic, analgesic, and antispasmolytic effects [111–114].
Toxicology
No toxic effect of crushed black seed was observed by
administrating high doses of NS [28 g/kg orally] in rabbits
[115, 116]. The seeds have very low degree of toxicity with
no significant adverse effects on liver or kidney functions;
however, two cases of contact dermatitis were detected
following topical use in humans [17]. In an animal study,
NS extracts were relatively nontoxic in acute toxicity test,
but the aqueous extract showed possible hepatic adverse
effects [117].
Zaoui et al. [115] studied the acute and chronic toxicities
of NS fixed oil in mice and rats. Changes in key hepatic
enzymes levels, including aspartate-aminotransferase, ala-
nine-aminotransferase, and gamma-glutamyltransferase
and histopathological modifications in the cardiac, hepatic,
renal, and pancreatic tissues were not observed in rats
treated with NS after 3 months of treatment. Although the
investigators reported a wide margin of safety for thera-
peutic doses of NS fixed oil, the count of leukocytes and
platelets decreased significantly, compared to control val-
ues, while hematocrit and hemoglobin levels increased
significantly. In another experimental study, Al-Ali et al.
[21] reported LD50 values of 10–15 times and 100–150
times greater than doses of thymoquinone reported for its

anti-inflammatory, antioxidant, and anticancer effects.
They concluded that thymoquinone is a relatively safe
compound, particularly when given orally.
Conclusion
The multiple uses of NS in folk medicine encouraged many
investigators to isolate its active components. A large
number of in vitro and in vivo studies have been conducted
on laboratory animals and a few in humans in order to
investigate its pharmacological properties and utilities in
different medical aspects. NS seeds and extracts have been
shown to have beneficial effect on diabetes mellitus, insulin
resistance syndrome, total lipid profile, and cardiovascular
system, as well as antiplatelet actions. In addition, pre-
treatment with NS oil decreased cyclosporine A, cyclo-
phosphamide, and doxorubicin injury in animal heart.
Based on the current review, it has been concluded that NS
has a broad spectrum of therapeutic potential especially in
cardiovascular diseases. Further, long-term human trials
are required to establish the therapeutic utility of this
ancient alternative medicine.
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