Review on Clinical Trials of Black Seed (Nigella sativa ) and Its Active Constituent, Thymoquinone

Abstract

Objectives
Nigella sativa (black seed or black cumin), which belongs to the Ranunculacea family, is an annual herb with many pharmacological properties. Among its many active constituents, thymoquinone (TQ) is the most abundant constituent of the volatile oil of Nigella sativa (N. sativa) seeds, and it is the constituent to which most properties of this herb are attributed.

Methods
PubMed-Medline, Scopus, and Web of Science databases were searched to identify randomized control trials (RCTs) investigating the therapeutic effects of N. sativa and/or TQ. In this review, we investigated the clinical uses of N. sativa and TQ in the prevention and the treatment of different diseases and morbidity conditions in humans.

Results
Black seed and TQ are shown to possess multiple useful effects for the treatment of patients with several diseases, such as inflammatory and auto-immune disorders, as well as metabolic syndrome. Also, other advantages, including antimicrobial, anti-nociceptive and anti-epileptic properties, have been documented. The side effects of this herbal medicine appear not to be serious, so it can be applied in clinical trials because of its many advantages.

Conclusion
Some effects of N. sativa, such as its hypoglycemic, hypolipidemic and bronchodilatory effects, have been sufficiently studied and are sufficiently understood to allow for the next phase of clinical trials or drug developments. However, most of its other effects and applications require further clinical and animal studies.

Full text

Review on Clinical Trials of Black Seed (
Nigella sativa
)
and Its Active Constituent, Thymoquinone
Alireza Tavakkoli1, Vahid Mahdian2, Bibi Marjan Razavi3 and Hossein Hosseinzadeh4,*
Abstract
Objectives: Nigella sativa (black seed or black cumin),
which belongs to the Ranunculacea family, is an annual
herb with many pharmacological properties. Among
its many active constituents, thymoquinone (TQ) is
the most abundant constituent of the volatile oil of Ni-
gella sativa (N. sativa) seeds, and it is the constituent to
which most properties of this herb are attributed.
Methods: PubMed-Medline, Scopus, and Web of Sci-
ence databases were searched to identify randomized
control trials (RCTs) investigating the therapeutic eects
of N. sativa and/or TQ. In this review, we investigated
the clinical uses of N. sativa and TQ in the prevention
and the treatment of dierent diseases and morbidity
conditions in humans.
Results: Black seed and TQ are shown to possess multi-
ple useful eects for the treatment of patients with sev-
eral diseases, such as inammatory and auto-immune
disorders, as well as metabolic syndrome. Also, other
advantages, including antimicrobial, anti-nociceptive
and anti-epileptic properties, have been documented.
e side eects of this herbal medicine appear not to be
serious, so it can be applied in clinical trials because of
its many advantages.
Conclusion: Some eects of N. sativa, such as its
hypoglycemic, hypolipidemic and bronchodilatory
eects, have been suciently studied and are su-
ciently understood to allow for the next phase of clini-
cal trials or drug developments. However, most of its
other eects and applications require further clinical
and animal studies.
1. Introduction
Nigella sativa (black seed or black cumin), which be-
longs to the Ranunculacea family, is an annual herb
with many pharmacological properties [1]. e use of
N. sativa (NS) seeds and oil in traditional remedies goes
back more than 2000 years, and the herb is described
as ‘the Melanthion’ by Hippocrates and Discroides [2].
Black seeds and their oil have a long history of folklore
usage in the Indian and the Arabian civilizations as
food and medicine and have been commonly used as
treatment for a variety of health conditions pertaining
to the respiratory system, digestive tract, kidney and
liver functions, cardiovascular system, and immune
system support, as well as for general well-being [3, 4].
NS contains many active components, such as thymo-
quinone (TQ), alkaloids (nigellicines and nigelledine),
saponins (alpha-hederin), avonoids, proteins, fatty
acids, and many others, that have positive eects in
the treatment of patients with dierent diseases [5, 6].
TQ is the most abundant constituent in the volatile oil
of NS seeds, and most of the herb’s properties are at-
tributed to it.
Cell culture studies and animal models have indicat-
Review article
Key Words
black seed, clinical trials, diseases, Nigella sativa, safety,
thymoquinone
ISSN 2093-6966 [Print], ISSN 2234-6856 [Online]
Journal of Pharmacopuncture 2017;20[2]:107-111
DOI: https://doi.org/10.3831/KPI.2017.20.014
This is an Open-Access article distributed under the terms of the Creative Commons
Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/)
which permits unrestricted noncommercial use, distribution, and reproduction in any
medium, provided the original work is properly cited.
This paper meets the requirements of KS X ISO 9706, ISO 9706-1994 and ANSI/NISO
Z39.48-1992 (Permanence of Paper).
*Corresponding Author
Hossein Hosseinzadeh. Pharmaceutical Research Center, Department of Pharmacody-
namics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences,
Mashhad, Iran.
Tel: +98-51-1881-9042 Fax: +98-51-1882-3251
E-mail: hosseinzadehh@mums.ac.ir
ⓒ 2017 Korean Pharmacopuncture Institute http://www.journal.ac
Received: Apr 28, 2017 Reviewed: Aug 21, 2017 Accepted: Aug 30, 2017
1 
DepartmentofPharmacognosy,SchoolofPharmacy,MashhadUniversityofMedicalSciences,Mashhad,Iran
2StudentResearchCommittee,SchoolofMedicine,MashhadUniversityofMedicalSciences,Mashhad,Iran
3 
TargetedDrugDeliveryResearchCenter,DepartmentofPharmacodynamicsandToxicology,SchoolofPharmacy,MashhadUniversity
ofMedicalSciences,Mashhad,Iran

http://www.journal.ac
108
ed several therapeutic potentials, such as anti-cancer [5,
7-9], antimicrobial [10, 11], analgesic [12, 13], antipyretic
[14], contraceptive and anti-fertility, anti-oxytocic [3], anti-
tussive [15], anti-inammatory [12, 16], and anti-oxidant
[17-19] potentials, for black seed and its active component
TQ. NS or TQ anticancer activity has been demonstrated
for blood, breast, colon, pancreatic, liver, lung, brosar-
coma, prostate, and cervix cancer cell lines and in animal
models of lung, kidney, skin, colon, and breast cancer [7].
Black seed’s antimicrobial eects include those on gram-
negative and gram-positive bacteria, viruses, parasites,
Schistosoma, and fungi pathogens [10]. NS was also found
to be able to relieve the symptoms of or cure patients with
several diseases, such as hypertension, dyslipidemia, met-
abolic syndrome, diabetes [5, 20, 21], asthma [3], convul-
sion [22-24], and natural and chemical toxicities [25, 26].
Additionally, a suggestion was made that NS and TQ uti-
lization could prevent many disorders [6], including neu-
robehavioral [27], kidney [28, 29], and liver [4] disorders.
For these reasons, in this review, we investigated the clini-
cal uses of NS and TQ in the prevention and treatment of
dierent diseases and morbidity conditions in humans.
2. Methods
PubMed-Medline, Scopus, and Web of Science databases
were searched to identify randomized control trials (RCTs)
investigating the therapeutic eects of NS and/or TQ. We
reviewed the existing literature published until April 2016
by using the following keywords: "Nigella sativa'', "black
cumin'', "black seeds'', "thymoquinone'', and "patient'',
"clinic'' or "clinical trial''. All studies assessing the eects
of NS or TQ, topical use or oral intake, on human health
conditions were included.
3. Results
3.1. Safety
Administration of NS oil (5 mL/day) to healthy volunteers
for 8 weeks was reported not to have any notable liver,
kidney, or gastrointestinal side eects [30, 31]. NS oil in-
take (equivalent to oil obtained from 0.7 g of seeds) for 40
days showed reasonable kidney and liver safety in patients
with type 2 diabetes mellitus (DM); neither did it alter the
platelet or the total leukocyte count [32]. Another study
performed on 39 centrally obese men demonstrated that
intake of NS seeds (3 g/day for 3 months) had no detect-
able side eects [33]. Qidwai et al reported that the admin-
istration of NS seeds (2 g/day for 6 weeks) did not aect the
serum alanine aminotransferase (ALT) or the serum creat-
inine (Cr) levels in adults [34]. Furthermore, NS at doses of
1, 2 and 3 g/day for 3 months did not adversely aect either
the renal or the hepatic functions of diabetic patients [35].
Another study revealed that NS seed powder intake for 40
days caused no signicant change in total leukocyte and
platelet count [36].
Treatment with NS tea (5 g/day) added to the usual oral
anti-diabetic drugs, diet, and exercise for 6 months showed
signicant decreases in aspartate aminotransferase (AST),
ALT, serum total, direct and indirect bilirubin, serum Cr,
and blood urea levels in type 2 diabetic patients, as well as
improved liver and kidney functions [37]. e intake of NS
extract (200 or 400 mg/day) for 2 months was also reported
to cause no observable complications in patients with mild
hypertension [38].
No adverse eects were reported in applications of NS
oil twice daily for six months to the lesions of vitiligo pa-
tients [39]. Intake of NS oil (0.05 mL/kg/day) in osteopenic
postmenopausal women for three months showed no
benecial eects; however, no adverse side eects were
produced, either [40]. In another study conducted on Ira-
nian infertile men in order to assess the impacts of NS oil
(5 mL/day) on abnormal semen quality, no side eects
were observed [41]. Whereas no severe side eects were
reported in administration of NS oil (5 mL/day) to func-
tional dyspeptic patients, some mild adverse impacts were
observed, including nausea, bloating, and burning sensa-
tion [42]. On the other hand, some cases of epigastric pain
and hypoglycemia were reported as adverse eects when
NS oil capsules were used to treat patients with hepatitis
C virus (HCV) [43]. Dirjomuljono et al demonstrated the
safety of NS extract (1,080 mg/day) when used to treat pa-
tients with acute tonsillopharyngitis [44]. In another study
that investigated the anti-cestodal eects of NS powdered
seeds (40 mg/kg body weight) on children infected with
cestodes, no serious side eects were reported [45].
Treatment of seasonal allergic rhinitis patients with NS
seeds (250 mg/day) for two weeks has been reported not
to cause any adverse eects [46]. However, some patients
with allergic rhinitis when treated using nasal drops of
NS oil showed nasal dryness [47]. Dogar et al conrmed
that side eects produced by treatment of children with
acute lymphoblastic leukemia (ALL), aged between 2 - 18
years, with NS powder (40 mg/kg in two equal doses for 3
months), along with conventional therapy, were remark-
ably less than they were for L-asparaginase and conven-
tional therapy (note: conventional therapy includes dau-
norubicin, vincristine, and prednisolone). us, one can
conclude that NS powder, as an anti-cancer agent, is a
benecial substitute for L-asparaginase in the treatment of
patients with ALL [48].
Nevertheless, in a patient suering from DM, along with
coronary artery disease and hypertension, acute renal fail-
ure due to the use of NS tablets (2,000 – 2,500 mg/day) was
reported to have occurred 6 days after the start of treat-
ment [49]. Bamosa suggested that this adverse eect could
not have been related to NS because other clinical trials
with many more human subjects had demonstrated the
safety of NS in higher doses over longer periods of intake
and that the adverse eect could probably be attributed
to contamination of the tablets with other products [50].
Ibraheim also reported that only the total oil showed sig-
nicant increases in the AST and the ALT levels while both
the oil and the crushed seeds showed signicant increases
in the
γ
-GT and the alkaline phosphatase (ALP) activities
[51]. A case of systemic and contact bullous drug eruption
as erythematous plaques with vesicles and bullous lesions
because of topical application and digestion of NS oil was
Journal of Pharmacopuncture 2017;20(2):107-111

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Journal of Pharmacopuncture 2017;20(2):107-111
Study design Population
Part of the herb, dose,
and duration of treat-
ment
Result References
Randomized,
double-blind,
placebo-controlled
trial
72 Type 2 DM patients
(men and women aged
30 - 60 years old)
NS oil (3 g/day)
12 weeks
↓ BMI, insulin level and insulin
resistance as well as HDL-C as
compared with baseline ,
↓ FBS, TG, LDL-C and HbA1c as
compared to the placebo group
[77]
-
41 Type 2 DM patients
(men and women aged
30 - 60 years old)
NS oil (equivalent to
oil obtained from 0.7 g
of seeds)
40 days
↓ FBS ,↑ insulin, but reversed
after 40 days of placebo adminis-
tration
[36]
Prospective study
60 patients with insulin
resistance (men and
women)
NS oil (5 mL/day) +
atorvastatin (10 mg/
day) and metformin
(1 g/day)
6 weeks
↓ TC, LDL-C and FBS [78]
Randomized,
double blind,
placebo-controlled
clinical trial
43 Type 2 DM patients
(men and women)
NS oil extract
(1 g/day)
8 weeks
↓ TG, LDL-C, TC, and LDL-C to
HDL-C ratios as compared to the
placebo
[79]
-41 type 2 DM patients
(men and women)
NS tea (5 g/day) +
usual oral anti-dia-
betic drugs, diet, and
exercises
6 months
↓ FBG, PPBG and HbA1c [37]
-94 type 2 DM patients
(men and women)
NS seeds 2 g/day or 3
g/day
12 weeks
↓ FBG, 2hPG, and HbA1c,
↓ Insulin resistance ,
↑
β
-cell function; no signicant
change in body weight
[35]
NS seeds 1 g/day,
12 weeks insignicant changes [35]
-
41 type 2 DM patients
(men and women aged
30 - 60 years old)
NS seed powder,
40 days
↓ FBG, TC, LDL-C and TG,
↑ HDL-C and insulin; all men-
tioned values except HDL signi-
cantly reversed again after 40 days
of placebo intake
[36]
Table 1 Eects of Nigella sativa supplementation on patients with diabetes
DM, Diabetes mellitus; NS, Nigella sativa; BMI, Body mass index; HDL-C, High density lipoprotein-cholesterol; TG, Triglyceride; LDL-
C, Low density lipoprotein-cholesterol; HbA1c, Haemoglobin A1c; FBS, Fasting blood sugar; TC, Total cholesterol; FBG, Fasting blood
glucose; PPBG, Postprandial blood glucose; 2hPG, 2 hours postprandial glucose.
reported [52]. In addition, another report showed that the
use of NS at 5 g/day inhibited CYP2D6- and CYP3A4-me-
diated metabolism of dextromethorphan in healthy hu-
man volunteers, showing that it may interact with other
CYP2D6 and CYP3A4 substrates [53].
Taken together, NS has been established as a safe herbal
product. Nevertheless, according to the mentioned stud-
ies, some adverse eects, including nausea, bloating, and
burning sensation, have been reported after administra-
tion of NS oil in functional dyspeptic patients, and a slight

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110
increase in liver and kidney enzymatic markers has been
shown following consumption of NS oil and crushed seeds.
3.2. Metabolic syndrome
Metabolic syndrome is a cluster of cardio-metabolic
conditions that include obesity, insulin resistance, ather-
ogenic dyslipidemia, and high blood pressure (BP) [54]
and is a major contributor to the development of diabetes
[55]. A RCT done on 60 patients with metabolic syndrome
showed that NS oil (5 mL/day) used in combination with
atorvastatin and metformin could decrease fasting blood
sugar (FBS), LDL, and TC signicantly after six weeks
of use, but had no signicant eect on body mass index
(BMI) or waist circumference (WC) [56].
Another study by Amin et al evaluated the eect of black
seeds (1.5 g/day) alone and concurrent with turmeric
(900 mg and 1.5 g/day, respectively) on 250 patients with
metabolic syndrome. e results show that NS and tur-
meric alone improved BMI, WC and BF% after 4 weeks,
compared to baseline. Combination therapy improved
all parameters including BMI, BF%, WC, hip circumfer-
ence (HC), BP, total cholesterol (TC), triglyceride (TG),
and C-reactive protein (CRP) except HDL-cholesterol with
lower FBG and LDL-cholesterol as compared to placebo
after four weeks. After 8 weeks, NS reduced lipids and FBG,
whereas turmeric decreased LDL-cholesterol and CRP.
Combination therapy showed an improvement in all pa-
rameters and reduced BF%, FBG, cholesterol, TG, LDL-
cholesterol, CRP and increased HDL-cholesterol [57].
In another study, premenopausal women underwent the
following protocol: 12-week administration of NS-powder
capsules (1,600 mg/day), a 2-week washout period, and
12-week administration of a placebo, and vise versa. e
authors of the study concluded that NS could help to con-
trol weight gain, the lipid prole, and the blood glucose
and hormonal levels [58]. According to a clinical trial by
Najmi et al, NS (500 mg/day) after 8 weeks was able to im-
prove the ecacy of the therapeutic protocol (metformin
+ atorvastatin + aspirin) in patients with metabolic syn-
drome and poor glycemic control so that NS-treated pa-
tients indicated signicant improvements in their FBG,
postprandial blood glucose (PPBG), haemoglobin A1c
(HbA1c), and LDL-C levels [59].
e eects of NS and TQ on dierent components of met-
Journal of Pharmacopuncture 2017;20(2):107-111
Table 2 Clinical eects of Nigella sativa supplementation on the nervous system
NS, Nigella sativa.
Study design Population
Part of the herb, dose,
and duration of treat-
ment
Result References
Double-blinded
crossover clinical trial 23 epileptic children
Water extract of black
seed (40 mg/kg/8 h),
10 weeks
Signicant reduction of
mean frequency of seizures [80]
Pilot, double-blinded
crossover clinical trial 22 epileptic children ymoquinone
(1 mg/kg), 10 weeks
Signicant reduction of
frequency of seizures [81]
Prospective,
randomized,
single-blinded,
controlled,
crossover pilot study
30 intractable
epileptic patients
40 - 80 mg/kg/day of
black seed oil,
10 weeks
No benecial eects in the
frequency and
severity of seizures
[82]
Placebo-controlled
clinical trial
40 healthy
elderly volunteers
500 mg NS seed cap-
sule twice a day,
9 weeks
Improvement of cognition,
memory, and attention [83]
Placebo-controlled
clinical trial
48 healthy
adolescent males
500 mg NS capsule
once daily, 4 weeks
Enhancements of mood,
anxiety, and cognition [84]
- 35 male opiate addicts 500 mg NS daily,
12 weeks
Signicant reduction of
withdrawal eects [85]
Randomized, triple-
blind, active, and
placebo-controlled
clinical trial
52 women with cyclic
mastalgia
Topical 600 mg
NS oil twice a day,
2 months
Signicant improvement of
the pain scores [86]

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Journal of Pharmacopuncture 2017;20(2):107-111
abolic syndrome and cardiovascular disease risk factors,
including high BP, obesity, dyslipidemia, and high blood
glucose, have been established [21]. e clinical uses of NS
and TQ in the prevention and treatment of these factors
will be discussed in subsequent subsections.
3.3. Hypertension
Hypertension (HT) is a lifestyle-related disease, and di-
etary modications are eective for its management and
prevention. In a study performed by Dehkordi and Kam-
khah, which evaluated the anti-hypertensive eect of NS,
the intake of NS extract (200 or 400 mg/day) for 2 months
was reported to decrease both the systolic and the diastolic
BP in patients with mild HT as compared with the baseline
and the placebo values [38]. Another study by Huseini et al
on healthy volunteers who received NS oil (5 mL/day) for
two months revealed the hypotensive eect of NS, with the
systolic and the diastolic BP being lowered signicantly as
compared with both the placebo and the baseline values
[31].
3.4. Obesity
Obesity, dened as excess fat mass, increases the risks for
multiple metabolic diseases, such as type 2 diabetes, car-
diovascular disease, and several types of cancer [60]. Some
RCTs demonstrated that NS oil in combination with a low-
calorie diet decreased weight in obese women in compari-
son to the placebo level [61, 62]. It also caused the super-
oxide dismutase (SOD) level to be elevated [61] and the TG
and the LDL-C levels to be decreased [62].
Another study was performed on 39 centrally obese men
to evaluate the eect of NS on body weight, WC, and some
biochemical parameters [33]. e results of that study
showed that intake of NS seeds (3 g/day for 3 months)
caused a very signicant reduction in body weight and
WC, but insignicant reductions in the serum free testo-
sterone level, as well as the systolic and the diastolic BP,
and an insignicant increase in the adiponectin level. e
reduction of serum free testosterone in the control group,
who received two capsules of 750 mg our twice daily, was
more than it was in the treatment group, thus indicating
that NS can inhibit the decrease in the serum free testo-
sterone level.
3.5. Dyslipidemia
Dyslipidemia is dened as the derangements of one or
more of the lipoproteins in blood, such as elevated TC,
LDL-C, and/or TG, or low levels of HDL-C alone [63].
Moeen-ud-din et al reported that the intake of 2 teaspoons
of NS seeds for 6 weeks by hyperlipidemic patients de-
creased their LDL-C (P-value < 0.001) and increased their
HDL-C (P-value < 0.01) as signicantly as niacin [64]. e
results of another RCT indicated that compared to mineral
oil, administration of NS oil (5 mL/day) to healthy volun-
teers for 8 weeks induced signicant decreases in the fast-
ing blood cholesterol, LDL, TG, glucose, and HbA1C levels
[30]. Administration of NS seeds (two spoons/day) to male
and female hyperlipidemic patients for 4 weeks signi-
cantly (P-value < 0.001) increased HDL-C and decreased
body weight [65].
Menopausal women are one of the high risk groups for
developing dyslipidemia. In a study by Ibrahim et al, the
administration of powdered NS seeds (1 g/day) over a two-
month intervention was found to decrease signicantly
the TG, LDL-C and TC levels, but to increase the HDL-C
level [66]. However, one month after cessation of treat-
ment, the lipid proles in the NS-treated group tended to
change towards the pretreatment levels. Another clinical
trial done for a similar duration showed that a supplement
of powdered NS seeds (1 g/day) could improve some bio-
chemical parameters, including the lipid prole and blood
glucose, in menopausal women, but had no signicant ef-
fect on their body weight [67].
According to a World Health Organization (WHO) report,
coronary heart disease is a major cause of mortality in the
world [68]. e results of a study which examined the ef-
fects of NS on the lipid proles in patients with stable coro-
nary artery disease indicated that intake of NS powder (500
mg/day) for 6 months concurrent with statin (10 - 20 mg/
day) both decreased the serum levels of TG, VLDL, LDL,
and TC and elevated the HDL level signicantly whereas
statin alone decreased neither the TG, VLDL, LDL nor TC
level [69].
In healthy female volunteers, administration of both
crushed seeds and the formulated total oil of NS caused
signicant reductions in the prolactin, glucose, triglycer-
ide, and cholesterol levels. Additionally, administration
of the crushed seeds caused a signicant increase in the
white blood cell count (WBC) and the hemoglobin level
whereas administration of NS oil only increased the hemo-
globin level signicantly [51]. In another study, Bamosa et
al suggested that the administration of NS at 2 g/day for 2
weeks decreased the blood levels of both glucose and cho-
lesterol in healthy volunteers [70].
A large RCT compared the eects of simvastatin (10 mg/
day) alone and concurrent with NS seeds (500 mg/day) and
garlic oil (0.625 mg/day) on the lipid prole in 258 patients
with hyperlipidemia over an 8-week treatment [71]. In that
study, a comparison of mean values between the two treat-
ment groups indicated a highly signicant dierence (P =
< 0.01) for cholesterol, TG, non-HDL, and LDL reductions
and a signicant dierence (P = 0.03) for HDL elevation
[71]. Sabzghabaee et al reported that the TC, LDL, and TG
serum levels in hypercholesterolemic patients who took
NS at 2 g/day for 4 weeks decreased signicantly [72]. e
uses of NS extract at 200 and 400 mg/day for 2 months were
also reported to have decreased both the total and the LDL
cholesterol in patients with mild HT as compared with the
baseline [38].
Of course, some controversies exist in the clinical trial
results. Qidwai et al reported that NS seeds (2 g/day) ad-
ministration had not aected the BMI, waist-hip ratio, BP,
FBS or serum lipids in adults after 6 weeks of use [34]. Un-
like pervasive evidence for the eects of NS use on the lipid
prole, the administration of powdered NS seeds was re-

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112
Figure 1 Schematic description for the eects of Nigella sativa in dierent parts of the human body
ported to have had no signicant eect on BP, serum lipid
levels, blood sugar, or body weight in adults [73]. According
to some meta-analyses, overall, the use of NS was shown
to reduce the plasma levels of TC, LDL-C and TG, but its
eect on HDL-C was not signicant [74, 75]. Whereas the
use of NS seed oil was observed to have greater eects on
the serum TC and the LDL-C levels, versus the use of seed
powder, elevation of the HDL-C levels was found only after
supplementation with NS seed powder [75].
3.6. Diabetes
DM is characterized by chronic elevation of blood glu-
cose, which is a central factor in the production of reactive
oxygen species (ROS) that, in turn, promote cellular dam-
age and contribute to the development and progression
of diabetic complications [76]. In a report by Heshmati et
al, although the administration of NS oil at 3 g/day for 12
weeks was stated to have caused insignicant decreases in
the BMI, insulin level, and insulin resistance, as well as an
increase in the HDL-C level, in patients with type 2 diabe-
tes, the FBS, TG, LDL-C, and HbA1c levels were observed
to have been lowered signicantly in the intervention
group as compared to the placebo group [77].
Another clinical trial showed that NS oil intake (equiva-
lent to oil obtained from 0.7 g of seeds) for 40 days caused a
signicant reduction of FBS and a signicant rise of insulin

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Table 3 Eects of Nigella sativa supplementation on patients with some diseases of the respiratory system
NS, Nigella sativa.
Disease Study design Population
Part of the herb,
dose, and duration
of treatment
Result References
Lower
respiratory
tract
illnesses
-15 asthmatic
patients
NS boiled extract
(50 and 100 mg/kg )
NS was less eective than
theophylline and salb-
utamol, on pulmonary
function tests
[96]
Controlled
clinical trial
29 asthmatic
adults
15 mL/kg/day of
0.1% NS boiled
extract, 3 months
Prophylactic eects of NS
on asthmatic patients [97]
Prospective,
randomized,
open study
84 patients of
wheeze associated
LRTI
NS oil (0.1 mg/kg),
14 days
More benecial eects in
reducing the pulmonary
index and improving the
peak expiratory ow rate
[98]
randomized,
double-blind,
placebo-
controlled trial
40 chemical war
victims
0.375 mL/kg/day of
50g NS boiled water
extract,
2 months
Prophylactic eect of NS
on chemical war victims [99]
Allergic
rhinitis
Single-blind
comparative
clinical trial
47 untreated adult
patients with
seasonal allergic
rhinitis
NS seeds
(250 mg/day),
2 weeks
Decreasing daytime, oph-
thalmic, and nighttime
symptoms
[46]
Double-blind
clinical trial
68 patients with
allergic rhinitis
Nasal drops of NS
oil (each drop: 15
mL oil), 6 weeks
Notable symptomatic
improvement of patients [47]
Tonsillo-
pharyngitis
comparative,
parallel, randomized,
double-blind,
placebo-controlled
study
186 acute tonsil-
lopharyngitis
patients
NSPN capsule
( 360 mg NS and
50 mg Phyllanthus
niruri extracts),
thrice/day, 7 days
Treatment of the symp-
toms of the disease [44]
in type 2 DM patients [32]. In still another study, the ad-
dition of NS oil at 5 mL/day to atorvastatin at 10 mg/day
and metformin at 1 g/day was shown to have induced sig-
nicant reductions in the TC, LDL-C, and FBS levels after
6 weeks of use in patients with insulin resistance [78]. Fur-
thermore, according to a study performed by Hadi et al on
43 type 2 diabetic patients, after an 8-week treatment, the
administration of NS oil extract at 1 g/day decreased the
serum levels of TG, LDL-C, and TC, as well as the LDL-C
to HDL-C ratio, signicantly in comparison to the placebo
[79]. Moreover, treatment with NS tea at 5 g/day added to
the usual oral anti-diabetic drugs, diet, and exercise for 6
months led to signicant decreases in the FBG, PPBG, and
HbA1c level in type 2 diabetic patients [37]. Another clini-
cal trial showed that the administration of NS at a dose of
2 g/day over a 12-week treatment caused signicant de-
creases in the FBG, 2hPG, and HbA1c levels without any
signicant change in body weight [35]. In that study, in-
sulin resistance, calculated by using a homeostatic model
assessment, was also reduced while
β
-cell function was
increased signicantly. However, a dose of 1 g/day caused
insignicant changes, and no further increments in the
benecial responses were observed with a dose of 3 g/day,
indicating that 2 g/day was the optimum dose. Bilal et al
reported the highly signicant decreases in the FBG, TC,
LDL-C and TG levels and increases in the HDL-C and the
insulin levels were observed in patients with type 2 diabe-
tes after 40 days of NS seed powder intake [36]. However,
in that study, all mentioned values, except the HDL level,
signicantly reversed again after 40 days of placebo intake.

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114
3.7. Nervous system
Akhondian et al demonstrated that treatment of intracta-
ble pediatric seizures with water extract of black seed (40
mg/kg/8 h) versus placebo, as an adjuvant therapy to anti-
epileptic drugs, led to a signicant reduction in the mean
frequency of seizures [80]. A similar clinical trial done by
the same author had similar outcomes, although TQ (1
mg/kg) was administered as an add-on therapy instead of
water extract of black seed [81]. On the other hand, anoth-
er study conducted by Shawki et al had a dierent result;
after administration of 40 - 80 mg/kg/day of black seed oil
as an adjuvant therapy for 4 weeks, no benecial eects on
the frequency and severity of seizures in intractable epi-
leptic children were observed [82].
In a placebo-controlled clinical trial addressing memory
and cognition, healthy elderly volunteers took a 500-mg
NS capsule twice a day over a period of 9 weeks [83]. At the
end of that period, through special tests, the authors ob-
served improved cognition, memory, and attention. Simi-
larly, another CT performed on healthy adolescent males
aged 14 to 17 years established the modulatory eects on
cognition, mood, and anxiety of NS taken in the form of a
500-mg NS capsule once a day for four weeks [84].
Sangi et al introduced NS administration as a eective
non-opiate treatment for opioid dependence [85]. ey
found that NS treatment oers some advantages in con-
trast with opiate treatments, such as relieving the with-
drawal eects, maintaining the physiological parameters,
and improving appetite.
3.8. Analgesic effects
Huseini et al showed that as compared with the topi-
cal administration of diclofenac, topical administration
of NS oil had signicant therapeutic eects on patients
with cyclic mastalgia without any adverse eects [86]. In
that study, 600 mg of NS oil (in the rst treatment group)
and 20 mg of topical diclofenac (in the second treatment
group) were applied to the painful area twice daily for two
months.
3.9. Dermatology
Vitiligo is an autoimmune skin disease occurring due to
the destruction of skin melanocytes that produce skin pig-
ment. A RCT comparing the ecacy of applying NS oil and
sh oil to the lesions of vitiligo twice a day for six months
indicated that the former is more eective than the latter in
reducing the size of the lesions [39].
Hand eczema is a pruritic papulovesicular dermatitis se-
verely inuencing the patient's quality of life. Youse et al
compared the eects of NS ointment, betamethasone, and
eucerin on the severity of hand eczema and the patients'
quality of life [87]. In that study, for new cases of hand ec-
zema in patients between 18 and 60 years of age the men-
tioned drugs were applied twice daily for 4 weeks. rough
particular measures, the authors concluded that NS may
be as eective as betamethasone in enhancing quality of
life and alleviating the severity of eczema and that both
were more eective than eucerin.
In contrast, for a comparison of the therapeutic eects of
NS oil ointment and aplacebo on patients with atopic der-
matitis (eczema), 20 patients were asked to apply NS oil on
one arm and a placebo on the other every day for 4 weeks
[88]. e authors of that study reported that no meaning-
ful dierence could be found in terms of the parameters
measured, e.g., severity, pruritis, transepidermal water
loss, and skin hydration, between the treatment with NS
oil ointment and with a placebo.
Arsenical keratosis manifests itself in both the palms of
the hands and the soles of the feet due to chronic arsenic
consumption caused by drinking contaminated water.
Taking capsules of NS oil (500 mg) and vitamin E (200 mg)
for eight weeks has been shown to reduce the body’s ar-
senic load, thereby contributing to an overall alleviation of
the symptoms in patients with this disease [89].
3.10. Infectious diseases
Infection with HCV often leads to chronic hepatitis,
which, in turn, results in liver cirrhosis and hepatocellular
carcinomas. A study conducted in Egypt on HCV patients
demonstrated that ethanolic extracts of NS and Zingiber
ocinale (Z. ocinale), alone and together, had bene-
cial eects on HCV patients; i.e., their liver function was
improved and the viral load was decreased [90]. In that
study, a mixture of these extracts was observed to be more
eective than each one alone. Patients included in that
study were treated with capsules containing 500 mg of NS
and/or Z. ocinale twice daily for one month. In a similar
study, HCV patients received capsules of NS oil (450 mg)
three times a day over a 3-month period. at treatment
led to the same results reported in Ref. 90, i.e., decreased
viral load and improved liver function [43].
Onifade et al conrmed that treatment of a sero-positive
human immunodeciency virus (HIV) infected man with
NS concoction (10 mL twice/day for six months) resulted
in the reduction of the viral load to an undetectable level
in 3 months, an elevation of the CD4 count, an allevia-
tion of the symptoms, and a sustained sero-reversion [91].
Similarly, another study conducted by the same author on
a sero-positive HIV infected woman revealed the ecacy
of NS and honey therapy (10 mL thrice/day for 1 year)
for sustained sero-reversion [92]. ese eects can be as-
cribed to the probable virucidal activity of NS [91].
e helicobacter pylori (H. pylori) bacterium can cause
many diseases, such as peptic ulcers and gastric cancer.
Infection with H. pylori has a high prevalence worldwide.
Salem et al stated that in a four-week course, the ecacy
of NS powder (2 g/day) administered together with ome-
prazole to eradicate an H. pylori infection in non-ulcer
dyspeptic patients was relatively the same as that of triple
therapy, although 1 g/day or 3 g/day of NS powder given
together with omeprazole was not as eective, indicating
that the optimal dose of NS was 2 g/day [93]. (Triple thera-
py includes clarithromycin, amoxicillin, and omeprazole.)
In a study conducted on children who were infected with

http://www.journal.ac 115
cestodes, the ecacy of single oral administration of NS
powdered seeds and ethanolic extract (40 mg/kg body
weight) was proven to reduce the percentage of fecal eggs
per gram, which means NS has an anti-cestodal eect
[45]. Furthermore, in a RCT in which 100 infected women
were included, the therapeutic eects of black seed cap-
sules (500 mg twice daily) used together with clotrimazole
vaginal cream on C. albicans vaginitis were compared
with those of placebo capsules (500 mg twice daily) used
in combination with the same vaginal cream [94]. In that
study, after a 7-day treatment, the black seed capsules
used with clotrimazole vaginal cream were more impres-
sive in reducing the symptoms of the disease, such as vagi-
nal itching, discharge, irritation, vulvovaginal redness and
inammation [94].
3.11. Reproductive system
Kolahdooz et al proved that treatment of infertile Iranian
men with 2.5 mL of NS oil twice a day for two months, in
contrast with a placebo treatment in the same manner,
could enhance sperm parameters, including sperm count,
motility and morphology, semen volume, pH, and its
round cells [41]. Other benecial eects of NS on Leydig
cells, reproductive organs, and sexual hormones in infer-
tile men have also been conrmed [95].
3.12. Respiratory system
As for lower respiratory tract illnesses (LRTI), Boskabady
et al investigated the antiasthmatic eects of NS boiled
extract (50 and 100 mg/kg), theophylline (5 mg/kg), and
salbutamol (200 μg) [96]. In that study, 15 asthmatic pa-
tients were recruited, and each patient received one of
these 4 treatments in random order at intervals of 48 hours
for 2 weeks. e results of that study demonstrated that
in spite of the fact that both doses of NS boiled extract
showed bronchodilatory eects, their ecacies for pul-
monary function test (PFT) elevation were less than those
of theophylline and salbutamol. e results also revealed
the prophylactic eects of NS boiled extract on adult asth-
matic patients. In another study, over a 3-month period,
the daily intake of 15 mL/kg of 0.1% NS boiled extract led
to more impressive improvements in the PFT parameters
and alleviations of the symptoms of asthma than the intake
of the placebo solution did [97]. Ahmad et al conducted a
study on 5- to15-year-old LRTI patients with wheezing and
investigated the benecial impacts of the standard treat-
ment alone and the standard treatment combined with the
use of NS oil [98]. e authors of that study concluded that
the standard treatment when administered with NS oil (0.1
mg/kg for 14 days) had more benecial eects in reducing
the pulmonary index and improving the peak expiratory
ow rate [98]. In another study, daily administration of
0.375 mL/kg of 50% NS boiled water extract, as compared
with a placebo solution to victims of chemical warfare, as
compared with a placebo solution, for two months eect-
ed meaningful improvements in the PFT measures and the
respiratory symptoms, indicating that the use of NS had a
prophylactic impact on victims of chemical warfare [99].
Allergic rhinitis (AR) is an inammatory response of the
nasal mucosa to natural allergens and is characterized by
sneezing, rhinorrhea, nasal congestion, and itching [47,
100]. Moreover, a study comparing the therapeutic eects
of NS seeds (250 mg/day) and montelukast (10 mg/day) on
patients with seasonal allergic rhinitis over a course of two
weeks illustrated that both improved the daytime and oph-
thalmic symptoms considerably, although NS was more
ecient in alleviating the nighttime symptoms [46]. Simi-
larly, Nikakhlagh et al showed the positive eects of NS oil
capsule consumption over four weeks on the symptoms of
allergic rhinitis, i.e., nasal mucosal congestion, nasal itch-
ing, runny nose, sneezing attacks, turbinate hypertrophy,
and mucosal pallor [100]. Like the previous studies, that
of Alsamarai et al demonstrated that nasal drops of NS oil,
in comparison with nasal drops of ordinary food oil, could
signicantly improve the symptoms of AR patients, as well
as their ability to tolerate exposure to allergens [47]. In that
study, each drop comprised 15 mL of oil, and the patients
applied 2 drops nasally (one in each nostril) 3 times dai-
ly for 6 weeks. In an additional study of AR patients who
underwent a month of allergen-specic immunotherapy
and then received treatment with NS seeds (2 g/d) dur-
ing the next month, in contrast with the AR patients who
only received immunotherapy for two months, the former
showed more progress in their immune status, e.g., PMN
functions and CD8 counts [101]. at study showed that
NS administration contributed to a more eective immu-
notherapy. According to a study by Oysu et al, some of the
nasal symptoms of geriatric patients, for example, nasal
dryness, obstruction, and crusting, can be signicantly
improved by using NS oil [102].
As for patients with tonsillopharyngitis, the results of a
study by Dirjomuljono et al indicated that NSPN capsules
containing 360 mg of NS and 50 mg of Phyllanthus niruri
extracts, as compared with a placebo, if given three times
a day for 7 days to patients with acute tonsillopharyngitis,
could signicantly alleviate the symptoms of the disease
due to their anti-inammatory and immuno-modulatory
eects [44]. In another study, which was undertaken on
patients with inhalation allergy, the benecial impacts of
NS oil on the immune status of those patients, including
enhancement of the NK cell count and percentage of lym-
phocytes, were conrmed [103].
3.13. Skeletal system
Rheumatoid arthritis (RA) is a chronic systemic disease
characterized by inammation of the joints, degeneration
of collagen bers in mesenchymal tissues, and atrophy of
bones. Although the etiology is not well understood, au-
toimmunity seems to play a role in the etiology of RA. A
study on 40 female RA patients who received placebo cap-
sules twice a day in the rst month and 500-mg NS oil cap-
sules twice a day in the next month observed that the use
of NS oil capsules notably improved the disease’s activity
score and alleviated its symptoms, which could be attrib-
uted to the modulatory eect of NS on the immune system

http://www.journal.ac
116
[104].
A clinical trial conducted on osteopenic postmenopausal
women showed that the intake of NS oil (0.05 cc/kg/d) for
three months had no considerable eects on bone turno-
ver markers [40]. Furthermore, in another clinical trial,
in which 15 osteoporotic postmenopausal women were
included, no benecial eects of consuming NS extract
(0.05 mL/kg/d for three months) on bone turnover were
observed [105].
3.14. Gastrointestinal system
Celiac disease (CD) is characterized by increased sen-
sitivity to gluten and by inammation and destruction of
the small intestine mucosa due to an autoimmune mecha-
nism. In a study by Osman et al, the prescription of a glu-
ten free diet (GFD) together with the consumption of a
NS oil capsule (450 mg) twice daily as dietary supplement
for one year was more eective than a GFD alone in the
treatment of patients with iron deciency anemia associ-
ated with refractory CD; i.e., the hematological and im-
munological indices and the duodenal histology recovery
were improved [106]. Dermatitis herpetiformis (DH) is an
autoimmune skin disease caused by CD and is character-
ized by itchiness, a burning sensation, and chronic derma-
titis. Similar to the former CT, adding NS oil capsules to a
GFD for a period of 6 months was found to enhance the
ecacy of a GFD in the treatment of the disease [107]. Fur-
thermore, Mohtashami et al. reported that administration
of a honey-based formulation of NS oil (5 mL NS oil/day),
in comparison with a placebo, for 8 weeks could signi-
cantly improve the symptoms, such as dyspepsia severity,
and decrease the rate of H. pylori infection in functional
dyspeptic patients [42].
3.15. Anti-toxicity effects
Leukemia is a tumoral growth of WBCs in the bone mar-
row and is caused by a malignant neoplasm of hemat-
opoietic stem cells. In ALL, which is the most common
childhood malignancy [108], increased numbers of lym-
phoblasts are present in the circulating blood and in dier-
ent tissues and organs [48]. A study by Hagag et al reported
that NS oil (80 mg/kg/day) administered for one week after
each methotrexate treatment could reduce hepatotoxicity
and improve the survival rate in ALL children undergoing
that treatment [108].
4. Discussion
is review article summarized dierent studies on the
clinical uses of NS and TQ in the prevention and the treat-
ment of dierent diseases. Results indicated that NS has
benecial eects when used in the therapies for various
diseases, including cardiovascular, nervous system, skin,
infectious, reproductive system, respiratory system, skel-
etal system, and gastrointestinal diseases. Taken together,
the role of NS in the treatment of dierent diseases is dis-
cussed in the following sentences.
Dyslipidemia plays an important role in the genesis of
cardiovascular diseases (CVDs) [71], and hypercholeste-
rolemia is the most important risk factor for atheroscle-
rosis [72]. Lipid abnormalities are accountable for 56% of
patients with heart disease and 18% of those with an in-
farction; further, it is associated with one third of deaths
worldwide. In this article, we reviewed 19 clinical trials
that reported the ameliorative eect of NS on the lipid pro-
le. is nding shows that the use of NS supplements can
improve the lipid prole and prevent CVDs both in healthy
people and hyperlipidemic patients. e exact mecha-
nisms of the lipid-modifying eects of NS are not known,
but might be associated with the inhibition of intestinal
cholesterol absorption, decreased hepatic cholesterol syn-
thesis, and up-regulation of LDL receptors [74].
On the other hand, dyslipidemia is an important risk fac-
tor responsible for cardiovascular disease in patients with
diabetes [109], so alleviation/elimination of lipid abnor-
malities is important in the prevention of the complica-
tions of diabetes [79]. us, keeping the lipid prole of dia-
betic patients in the normal range can improve their health
status, and NS intake, in combination with anti-diabetics
and statins or brates, can help diabetic patients to control
both dyslipidemia and blood sugar. We also reported the
results of 13 clinical trials that presented data on the hy-
poglycemic eect of NS, 8 of which included patients with
insulin resistance. e results showed that the use of black
seed could decrease the HbA1c (5 studies) and the PPBG
(2 studies) levels signicantly.
Obesity is typically associated with increased risk factors
of CVDs. erefore, a therapeutic approach that aims to
control body weight and the metabolic prole might be ef-
fective in preventing CVDs [62]. e results of this review
demonstrate that the use of NS may have a weight-lose ef-
fect in obese men and women. Because of the lipid-mod-
ifying, hypoglycemic, and weight-lowering eects of black
seed, its use in the treatment of patients with metabolic
syndrome may be benecial [21].
According to some studies reviewed, NS may be a useful
herb for improving sexual function because of its inhibito-
ry eect on prolactin [51] and excitatory eect on testoster-
one [33]. In addition, spermatogenesis can be stimulated
by NS [95]. Consequently, it presents a good option for use
in the treatment of infertile men. However, more studies
are needed due to the lack of an adequate number of stud-
ies proving this eect.
TQ has an antioxidant role, improves the body's defense
system, induces apoptosis, and controls the Akt pathway
[7]. Immune system modulation is one of the most impor-
tant properties of NS, and a number of studies have been
done in order to prove this signicant eect. In this article,
we reviewed ve studies that directly showed the immuno-
modulatory eect of NS [39, 44, 104, 106, 107]. In addition,
other investigations have demonstrated that NS may be an
optimum choice for treating patients with allergy-related
diseases, such as asthma, atopic eczema and allergic rhini-
tis [110].
Moreover, the anti-nociceptive eect of NS has been
widely investigated in animal models, and a few studies

http://www.journal.ac 117
have evaluated that eect in humans. In this paper, the
anti-microbial activities of NS against bacteria, viruses,
and parasites have also been highlighted. e conclusion
is that it can be used in the treatment of infectious diseases
[111].
e existing drugs for some diseases produce adverse side
eects, do not lead to complete recovery, or are sometimes
expensive. us, herbal medicines, such as NS, can be use-
ful alternatives; however, before such herbal medicines are
used extensively, many RCTs should be conducted in or-
der to evaluate and conrm the eects of herbal medicines
[46, 48, 108]. One obvious example is sero-reversion in
HIV-infected patients. Highly active anti-retroviral therapy
does not cause sero-reversion in HIV-infected patients.
Onifade et al proved that NS contributes to sustained sero-
reversion in patients with HIV infection [91, 92].
Some authorities, despite achieving positive outcomes
for the features of NS, suggest further investigations with
larger samples and groups, diverse doses of NS, and longer
periods of study [42, 83-85, 93, 97-99]. After the benecial
eects of NS have been conrmed, it can be used in treat-
ment protocols. In contrast, some authors have reached
results that conict with the traditional beliefs about NS.
Actually, the evidence for the positive eects of NS in the
treatment of osteopenic postmenopausal women and
intractable epileptic children is conicting [40, 82, 105].
erefore, more studies should be planned in these situ-
ations.
5. Conclusion
In conclusion, the use of black seeds and their active
constituent TQ has been shown to have multiple useful
eects in the treatments of patients with several diseases,
such as inammatory and auto-immune disorders, as well
as metabolic syndrome. In this study, we also reviewed
other advantages of NS, e.g., its antimicrobial properties,
anti-nociceptive and anti-epileptic impacts, etc. We found
that the side eects of this herbal medicine did not ap-
pear serious, so it can be applied in clinical trials because
most of its major eects have been shown to be benecial.
Some properties of NS, such as its hypoglycemic, hypoli-
pidemic, and bronchodilatory properties, are suciently
understood so that NS can be used for subsequent phases
of clinical trials or for drug development. However, most
of the other eects and applications of NS require further
clinical and animal studies.
Acknowledgment
e authors thank Mashhad University of Medical Sci-
ences, Mashhad, Iran.
Conflict of interest
e authors declare that there are no conicts of interest.
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