Pakistan J. Med. Res.

Vol.41, No.2, 2002

REVIEW ARTICLE

A review of the pharmaco-therapeutic effects of Nigella sativa

Muhammad A. Randhawa, Mastoor S. Al-Ghamdi

Department of Pharmacology, College of Medicine, King Faisal University, Dammam, Saudi Arabia

INTRODUCTION

N igella sativa (N. sativa) belongs to the botanical family of Ranunculaceae and
commonly grows in Europe, Middle East, and Western Asia. Coequal names of its
seed in Arab countries are Al-Habbah Al-Sawda, Habbet el-baraka, Kamoun Aswad, Schuniz
and Khodria. In Pakistan, India and Sri Lanka it is called as Kalvanji, Azmut, Gurat, Aof and
Aosetta; and in English language is known as black seed, black cumin and black caraway.

Table 1: Chemical composition, including active principles, of Sativa seed

Group Sub-group Components

Fixed oil Unsaturated fatty acids Arachidonic, eicosadienoic, linoleic, linolenic, oleic and
(32-40 %)* almitoleic acid12-13
Saturated fatty acids Palmitic, stearic and myristic acid12-15
Beta-sitosterol, cycloeucalenol,
cycloartenol, sterol esters and sterol glucosides

Volatile oil Nigellone, thymoquinone, thymohydroquinone,

(0.4-0.45 %)* dithymoquinone, thymol, carvacrol, α & β-pinene, d-limonene,
d-citronellol,
p-cymene and
2-(2-methoxypropyl)-5-methyl-1,4-benzenediol6,16-18
Proteins Amino acids Arginine, glutamic acid, leucine, lysine, methionine, tyrosine,
(16-19.9 %)* proline and threonine, etc.13
Alkaloids Nigellicine, nigellidine, nigellimine-N-oxide
Coumarins 6-methoxy-coumarin ,7-hydroxy-coumarin
7-oxy-coumarin19-23
Saponins: Triterpenes Alpha-hedrin24
Steroidal Steryl-glucosides, 25 acetyl-steryl-glucoside

Minerals Calcium, phosphorous, potassium, sodium and iron13,26

(1.79-3.74 %)*
Carbohydrates
(33.9%)*
Fiber (5.5 %)*
water (6 %)*

Seeds of N. sativa are frequently used in folk medicine in the Middle East and some Asian countries
for the promotion of good health and treatment of many ailments including fever, common cold,
headache, asthma, rheumatic diseases, various microbial infections and to expel worms from the
intestines. It is also used for scorpion and spider stings and bites of snake, cat and dog. In addition, it
is used as a flavoring additive to bread and prickles. 1,2

The multiple use of N. sativa in the folk medicine encouraged many investigators to isolate the
possible active components and to conduct in vivo and in vitro studies on laboratory animals and
human beings in order to understand its pharmacological actions. These include, immune
stimulation1, anti-inflammatory3, anti-cancer4, anti-microbial5,6, anti-parasitic7, anti-oxidant8,9, and
hypoglycemic effects10,11, etc. The chemical composition of N. sativa seed (including an account of its
active principles) has been summarized in Table 1.

Effect on Immune System:

As a natural remedy people take N. sativa seed or oil as a promoter of good health and for the
prophylaxis of common cold and asthma. In view of that El-Kadi and Kandil 1 investigated the effect
of N. astiva on immune system and reported that the administration of 1g twice daily in human
volunteers enhanced immune functions as manifested by improved helper T cell (T4) to suppressor T
cell (T8) ratio and an improved natural killer cell activity. However, there was a decrease in the
immune globulin (IgA, IgG and IgM) levels. Moreover, Haq et al 27 noticed that N. sativa enhanced
the production of interleukin-3 by human lymphocytes when cultured with pooled allogenic cells or
without any added stimulator. They also observed an increase in interleukin-1 beta (IL-1)
suggesting that N. sativa has an effect on macrophages as well.

In another study on mixed lymphocyte culture, Haq et al 28 observed that whole N. sativa seeds and its
purified proteins demonstrated stimulatory as well as suppressive effects depending upon the donor
and the concentration used. Stimulant effect was observed with fractionated N. sativa proteins (P1
and P2) with a maximum effect at 10 ug/ml. Suppressive effect was observed with N. sativa seeds
and high concentrations of all of its four proteins when lymphocytes were activated with poked-weed
mitogen. In culture medium with non-activated peripheral blood mononuclear cells and with
allogenic cells whole N. sativa produced large quantities of IL-1 beta, but no effect was seen on IL-4
secretion. The effect on IL-8 production was variable. However, a stimulatory effect of whole N.
sativa and its fractionated proteins was noticed on the production of TNF- in both non-activated
and mitogen activated cells.

The ethyl-acetate chromatographic fraction of ethanolic extract of N. sativa has also been reported to
potenciate cellular immune responses29.

Anti-inflammatory and Analgesic Effect:

In Saudi Arabia and neighbouring countries N. sativa oil is used as a topical treatment for pain and
stiffness in joints. This indication together with its use in bronchial asthma suggested for the
investigation of analgesic and anti-inflammatory effects of N. sativa. Houghton et al3 reported that
crude fixed oil of N. sativa and an active principle, thymoquinone, inhibited cycloxygenase and 5-
lipooxygenase pathways of arachidonate metabolism in rat peritoneal leukocytes. The effect was
demonstrated via the dose-dependent inhibition of the formation of thromboxane B 2 and leukotriene
B4. This effect was later confirmed in experimental animal studies conducted by Mutabagani and El-
Mahdy30 using N. sativa volatile oil and Al-Ghamdi31 using aqueous suspension of N. sativa crushed
seeds. In both studies formation of edema in rat hind paw was inhibited and these effects were
comparable to those of indomethacin and aspirin, respectively.

Al-Ghamdi31 also reported an analgesic effect of aqueous suspension of N. sativa seeds, comparable
to aspirin, as measured by hot plate test conducted in rats. However the suspension did not relieve
yeast-induced pyrexia in rats.
The mechanism of anti-inflammatory and analgesic effects seems to be related to the inhibition of
eicosanoid synthesis as suggested by the study of Houghton et al 3. Another possibility for the
analgesic action could be the activation of supraspinal mu (1)- and kappa-opioid receptors subtypes,
as elicited by the antagonistic effect of naloxone, naloxonazine and nor-binaltorphimine to
antinociceptive effects of N. sativa oil and thymoquinone32.

Anti-Cancer Effect:

The anticancer activity of N. sativa was first revealed by El-Kadi and Kandil 1 who observed
enhancement of natural killer (NK) cell activity ranging from 200-300 % in advanced cancer patients
receiving multimodality immunotherapy programme in which N. sativa was one of the components.
Later on, the anti-cancer effect of N. sativa was investigated both in vitro using cancer cell lines and
in vivo using animal models.

Topical application of N. sativa and Crocus sativus extracts inhibited two-stage initiation/promotion
(dimethylbenz-a-anthracene/croton oil) of skin carcinigenesis in mice by delaying the onset of
papilloma formation and reducing the number of papillomas per mouse. These extracts also restricted
20-methylcholanthrene induced soft tissue sarcomas in mice 4. Moreover, an active principle of N.
sativa containing fatty acids demonstrated, in vitro, 50% cytotoxic activities against Ehrilch ascites
carcinoma (EAC), Dalton’s lymphoma ascites and sarcoma-180 cells and, in vivo, completely
inhibited EAC tumour development in mice33.

Thymoquinone and dithymoquinone, active principles of N. sativa, had cytotoxic effect against
parental and multi-drug resistant human tumour cell lines which were over 10-fold more resistant to
doxorubicin and etoposide34. Similarly, thymoquinone reduced the incidence and multiplicity of
benzo-a-pyrene induced forestomach tumour in female Swiss albino mice by 70 % and 67 %,
respectively35. Ethyl-acetate column chromatographic fraction (CC-5) of ethanolic extract of N.
sativa also showed cytotoxic effect against different classes of cancer cell lines, such as, Hep G2,
Molt4 and Lewis lung carcinoma cells29.

More recently, CC-5 and alpha-hedrin (AH), which were isolated from CC-5, produced significant
dose dependent tumour inhibition rate comparable to cyclophosphamide treated group 24. Similarly,
thymoquinine inhibited 20-methylcholanthrene-induced fibrosarcoma in mice 35.

Anti-Microbial and Anti-Parasitic Actions:

The anti-bacterial effect of the phenolic fraction of N. sativa oil was first reported by Topozada et al 5.
Thymohydroquinone was later isolated by El-Fatatry 6 from the volatile oil of N. sativa and found to
have high activity against gram-positive microorganisms. Hanafi and Hatem 36 studied the
antimicrobial effect of diethyl-ether extract of N. sativa and reported that it had a concentration
dependent inhibition of gram-positive bacteria (represented by Staphylococcus aureus) and gram-
negative bacteria (represented by Pseudomonas aerogenosa and Escherichia coli). It also showed
synergistic effect with streptomycin and gentamycin and additive effect with spectinomycin,
erythromycin, tobramycin, doxycycline, chloramphenicol, nalidixic acid, ampicillin, lincomycin and
co-trimoxazole. In addition, the extract was found to have a concentration dependent inhibitory effect
against pathogenic yeast, Candida albicans. Recently, crude extracts of N. sativa were reported to
have a promising effect on multi-antibiotic resistant organisms including gram-positive and gram-
negative bacteria37.
Intra-peritoneal administration of N. sativa oil strikingly inhibited the virus titer in spleen and liver of
mice infected with murine cytomegalovirus 38. This action was possibly mediated by increasing the
number and function of M & phi as well as IFN- production.

Akhtar and Riffat7 investigated the anti-cestodal effect of N. sativa seeds and its ethanolic extract
when given orally to infected children. Both were effective in reducing the percentage of faecal eggs
per gram counts and the effect was comparable to niclosamide. Moreover, N. sativa menthol extract
(1ml/kg) and powder (200 mg/kg) showed high efficacy, comparable to Hapadex (netobimin, 20
mg/kg), against rumin fluke (Paramphistomum) in sheep39 and Nigella sativa oil also prevented liver
damage induced by Schistosoma mansoni infection in mice40.

Anti-Oxidant Activity:

N. sativa extracts and some of its active principles, like thymoquinone, have been shown to possess
protective effect against haematological, hepatic, renal and other toxicities induced by anti-cancer
drugs and some toxins. For example, N. sativa extract prevented the decreases in haemoglobin level
and leucocyte count caused by cisplatin in mice 8. Thymoquinon and fixed oil of N. sativa were also
reported to inhibit non-enzymatic peroxidation in ox brain phospholipid liposomes 3.

N. sativa along with cysteine, vitamin E and Crocus sativus protected cisplatin-induced
haematological, hepatic and renal toxicities 41. Thymoquinone protected isolated rat hepatocytes from
ter-butyl-hydro-peroxide-induced toxicity42. Thymoquinone also showed hepatoprotective effect
against CCl4 – induced toxicity in mice43. El-Dakhakhany et al44 have also reported the protective
effect of N. sativa oil against CCl4 and D-galactosamine induced hepatic toxicity in rats. In these
studies protection from liver toxicity was measured as a significant decrease in serum activities of
alkaline phosphatase, lactate dehydrogenase, malate dehydrogenase, aspartate aminotransferase, and
alanine aminotransferase, etc and a significant increase in glutathione reductase.

Badary et al35,45 observed the protective effect of thymoquinone on ifosfamide–induced Fanconi

syndrome in mice and doxorubicin-induced hyperlipidemic nephropathy in rats, respectively,
manifested as a significant improvement of phosphaturia, glucosuria, and elevated serum creatinine
and urea as well as a significantly improvement of renal glutathione depletion and lipid peroxide
accumulation.

Furthermore, Burits and Bucar46 found that N. sativa essential oil and its four constituents
(thymoquinone, carvacrol, t-anethol and 4-terpineol) had anti-oxidant effect in different chemical
assays, like diphenylpicrylhydracyl assay for non-specific hydrogen atom or electron
donating activity. They also observed OH-radical scavenging property in the assay for non-
enzymatic lipid peroxidation in liposomes and the deoxy-ribose degredation assay.

More recently, Turkdogan et al47 reported the protective action of N. sativa for carbon
tetrachloride induced liver fibrosis and cirrhosis in rabbits, as well as El-Sherbeny 48 reported
the protective effect of N. sativa against the genotoxic action of an herbicide, 2,4-D.

Anti-Histaminic Action :

The antihistaminic effect was first investigated by El-Dakhakhany 49 who reported the
protective action of thymoquinone and carbonyl fraction of N. sativa against histamine-
induced bronchospasm in guinea pigs. Furthermore, in an in vitro study, Chakarvarti50
demonstrated that nigellone, isolated from N. sativa, effectively inhibited the release of
histamine from mast cells, possibly through decrease in intracellular calcium and inhibition
of protein kinase C. These effects together with analgesic and anti-inflammatory actions,
perhaps, can be correlated with the use of N. sativa in eczema and asthma, for scorpion and
spider stings and for the bites of cat, dog and snake, recommended in the folk medicine2.

Effects on the Respiratory System:

In Saudi Arabia and neighbouring countries N. sativa seeds and oil are commonly used for
the treatment of asthma. Nigellone (a carbonyl polymer of thymoquinone) proved to be an
excellent prophylactic agent for both bronchial asthma and asthmatic bronchitis and was
more effective in children than adults 51,52. Sayed53 has also reported the use of N. sativa in
asthma in the traditional medicine.

However, El-Tahir et al54 observed that N. sativa volatile oil induced dose dependent increase
in the respiratory rate and the intra-tracheal pressure, which were antagonized by
mepyramine, atropine and reserpine but not by indomethacin, diethyl-carbamazine or
hydrcortisone. A central mechanism was suggested for these effects.

Apparently, these observations seem to be in contrary to the antihistaminic effect reported by

El-Dakhakhany49 and Chakarvart50 and its use in the folk medicine for asthma. However, in a
later study, aqueous extract of N. sativa competitively and the macerated extract non-
competitively antagonized methacholine induced contractions of isolated guinea-pig tracheal
chain55. Similarly, crude extract of N. sativa has also been shown to cause relaxation of
carbachol –, histamine – and K + – induced contractions of isolated guinea-pig trachea56.

Effect on Cardiovascular System:

In Arabian folk medicine whole seeds of N. sativa alone or in combination with honey or
garlic are promoted for the treatment of hypertension, which drew the attention of EL-Tahir
et al57 to investigate the effects of N. sativa on the cardiovascular system. Volatile oil and
thymoquinone produced a dose dependent decrease in the arterial blood pressure and the
heart rate. These effects were significantly antagonized by atropine, cyproheptadine,
hexamethonium and spinal pithing. However, reserpine only antagonized the effects of low
doses of volatile oil but not of thymoquinone. They suggested that these effects were
centrally mediated, mainly via the involvement of both the 5-hydroxytryptaminergic and
muscarinic mechanisms. Similarly, an oral dose of 0.6ml/kg/day of N. sativa extract
produced a significant hypotensive effect in spontaneously hypertensive rats comparable to
that of 0.5 mg/kg/day of oral nifedipine 58,59. This effect was concluded to be partially due to
the diuretic effect of N. sativa, which was comparable to 0.5 mg/kg/day furosemide or by
other mechanisms as mentioned above.

Effect on Genito-Urinary System:

In Unani medicie N. sativa is promoted for the treatment of oligomenorrhoea, to induce

menstruation and to treat infertility2. El-Naggar and El-Deib60 reported that N. sativa crude
oil induced uterine contractions both in vivo in pregnant rabbits and in vitro of non-pregnant
rat uteri. Similarly, Keshri et al61 found that the hexane extract of N. sativa exhibited mild
uterotropic activity and prevented pregnancy in rats when given on day 1-10 post-coitum.
On the contrary, Aqel and Shaheen62 reported that volatile oil of N. sativa inhibited
spontaneous contractions of rat and guinea pig uterine smooth muscle and those induced by
oxytocin. Similarly, treatment of pregnant rats with fixed oil of N. sativa for 2 weeks
significantly suppressed PGE2 and oxytocin – induced contractions of isolated rat uteri
treated with diethylstilboesterol, suggesting the potential use of N. sativa oil in the uterine
disturbances associated with prostaglandin and oxytocin induced increased contractility e.g.
some dysmenorrhoeas, premature deliveries and habitual abortions 63. These differences may
be due to the different doses, preparations and the animal species used.

Effect on Gastro-Intestinal Tract:

In Unani medicine N. sativa is used for stomachache and as a digestive, carminative,

laxative and anti-jaundice1. Oral N. sativa powder was reported to relieve flatulence by
Chopra et al64. While Nigellone, an active principle of N. sativa was found to antagonize
histamine induced contractions of guinea pig intestine. In addition, Mahfouz et al52 and El-
Dakhakhani65 reported a choleretic effect of N. sativa oil and its active principles
(thymoquinone, thymohydroquinone and dithymoquinone), respectively.

El-Dakhakhani et al66 investigated the effect of N. sativa oil on gastric secretion and ethanol-
induced ulcer in rats. Significant increase in mucin content, glutathione level as well as a
significant decrease in mucosal histamine content and ulcer formation, with a protection
ratio of 53.56 %, was found in the N. sativa oil pretreated group. More recently, the crude
extract of N. sativa was shown to cause a dose –dependent (0.1 – 3.0 mg/ml) relaxation of
spontaneous contractions of rabbit jejunum as well as inhibition of K + – induced
contractions in a similar dose range, suggestive of calcium channel blockade56.

Hypoglycemic effect:

Al-Awadi and Gumma10 have reported the use of a plant mixture containing N.sativa, Myrr, Gum
Olybanum, Gum Asafoetida and Aloe by diabetics in Kuwait. They confirmed the blood glucose
lowering effect of N. sativa, in combination with other herbs in rats. The mechanism of action was
later investigated and appeared to be due to the inhibition of hepatic gluconeogenesis 67. The volatile
oil of N. sativa alone also produced a significant hypoglycemic effect on normal and alloxan-induced
diabetic rabbits without changes in insulin levels 68. The hypoglycemic effect of N. sativa in
combination with other herbs on alloxan-induced diabetic rats was also reported by Eskander et al 69
and El-Shabrawy and Nada70. Furthermore, Bamosa et al11 reported a significant decrease in blood
sugar of healthy human volunteers treated with 1 gram of N. sativa capsules twice daily.

Effect on Blood:

In Kuwait some people use extract of N. sativa with natural fat for epistaxis. In view of that the
petroleum ether extract of N. sativa was studied for its action on blood coagulation and was reported
to shorten the whole blood clotting time, plasma clot time and kaolin-cephalin clotting time of male
rabbits when compared to control. In addition, a significant shortening of bleeding time in rats was
also observed. However, there were no significant effects on the thrombin time or prothrombin time
but the partial thromboplastin time was shortened while euglobulin time was prolonged 71.
In contrast, N. sativa fixed oil suppressed adenosine diphosphate – induced platelet aggregation in
both normal and diabetic rats63. Similarly, in a recent study it was observed that the menthol soluble
components of N. sativa oil including 2-(2-methoxypropyl)-5-methyl-1, 4-benzenediol, thymol and
carvacrol as well as 8 other related compounds had very strong inhibitory effect on arachidonic acid
-induced platelet aggregation. This platelet aggregation inhibitory effect was more potent than that of
aspirin72.

Bamosa et al11 reported a pattern of decreased levels of cholesterol and triglycerides (on days 7 and
14) of healthy human volunteers treated with 1 gram of N. sativa capsules twice daily. This effect
was later confirmed by El-Dakhakhani et al 66 using N. sativa oil (800 mg/kg orally for 4 weeks) in
rats showing a significant decrease in serum total cholesterol, low density lipoprotein and
triglycerides and an elevation of serum high density lipoprotein level. More recently, N. sativa oil in
rats has been shown to decrease the serum cholesterol, triglycerides and glucose levels as well as the
counts of leukocytes and platelets by 15.5, 22, 16.5, 35 and 32 %, respectively, while haematocrit and
haemoglobin levels increased by 6.4 and 17.4 %, respectively 58. However, Al-Jishi2 did not find any
changes in blood cells when N. sativa was given to normal rats.

CONCLUSIONS

N.sativa seed and its components are frequently used as a natural remedy for many ailments. A lot of
work has been done to evaluate the pharmacological basis of these uses. Most studies confirm its
value in folk medicine as analgesic, anti-inflammatory, anti-oxidant, anti-cancer, anti-microbial, anti-
parasitic, antihypertensive and as an immune stimulant. However, controversial results have been
reported for its effect on the respiratory system, blood coagulation and uterine motility. More work is
needed to determine the pharmacokinetics, pharmacodynamics and therapeutics of active
components and their interactions with modern drugs.

ACKNOWLEDGMENTS

We gratefully acknowledge the help of Dr. Abdullah O. Bamosa, Chairman Department of

Physiology, College of Medicine, King Faisal University, Dammam, Saudi Arabia, for the provision
of the locally published articles and theses related to studies on N. Sativa. Our sincere thanks are also
extended to Dr. E.B. Larbi (Professor of medicine and Clinical Pharmacology) and Dr. Obeid El-
treifi (Assistant Professor of Immunology) from the same college for reviewing the manuscript.

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