Black seed oil

Synonym(s): black cumin oil, black caraway oil, alpha hederin, Nigella sativa, thymoquinone

Nutrient group: plant extracts & active ingredients

Sources and physiological effects

Dietary sources
Black seed (Nigella sativa), also known as the gold of the paraohs, belongs to the buttercup family. Oil is obtained from its seeds, which is traditionally used as a natural drug for over 2000 years and is characterized by a spectrum of different bioactive plant ingredients. Among the best-known and most important active ingredients are thymoquinone and alpha-hederin.
Physiological effects
Liver	Thymoquinone prevents lipid peroxidation in the liver.
Anticarcinogen	Thymoquinone inhibits cell proliferation and supports apoptosis in tumor cells.
Immune system	Strengthens the natural immune response of T-cells and killer cells.

Recommended intake

Reference values for the intake of black seed oil
Children (2-16 years)	15-80 mg/kg bw/day ^(1)(2)(3)
Teenagers/adults (from 16 years)	3g/day

Detailed information

Black seed components

The cold-pressed oil from the seed of Nigella sativa is one of the important, traditionally used natural drugs in various cultural circles. Studies show that, in addition to phytochemicals such as thymohydroquinone, nigellone, some alkaloids (nigellidine and nigellicine) and flavonoids, the components contained thymoquinone and alpha-hederine in particular are promising chemopreventive substances and are probably responsible for the majority of the pharmacological effects. These include immunomodulating, hypoglycaemic, hypocholesterolaemic, anti-obesity, hepatoprotective, hypotensive, bronchodilator, analgesic, anti-inflammatory, antioxidant and cytoprotective properties as well as a cytotoxic and cytostatic effect on tumour cells. The main component thymoquinone has anti-inflammatory and antioxidant effects. It can upregulate the gene expression of antioxidants such as catalase, glutathione peroxidase and glutathione reductase. Furthermore, by scavenging free radicals, this substance reduces lipid peroxidation and thus the production of malondialdehyde, an important biomarker for oxidative stress. Furthermore, from a phytochemical point of view, Nigella sativa contains a wide range of health-promoting ingredients. The seeds of the plant contain valuable fatty acids - such as linoleic acid, oleic acid -, essential oils, minerals and vitamins.^1,2,3

Immunomodulating potential for use in allergies

Nigella sativa oil has long been used to prevent and alleviate the symptoms of allergic reactions. Clinical studies in patients with allergic rhinitis, asthma or atopic eczema support the efficiency of its use in this indication. In all studies, the patients showed an improvement in the subjective perception of the symptoms, along with the corresponding clinical parameters. Black cumin oil is evaluated as an effective adjuvant for the treatment of allergies.⁴ The successful use of black cumin in asthmatic diseases is attributed to the anti-inflammatory and relaxing effect on the bronchial tubes as well as to a pronounced antihistamine effect. According to this, black cumin as a prophylactic measure leads to a significant reduction in the frequency and intensity of asthma symptoms.^5,6 Furthermore, the seeds of black cumin are also successfully used for hay fever, pollen, dust and animal hair allergies and show a reduction in symptoms such as nasal itching, sneezing attacks and swelling of the nasal mucosa after only two weeks of supplementation.⁷ By suppressing inflammatory mediators such as prostaglandins and leukotrienes and by increasing T-cells and natural killer cell activity, black cumin oil also appears to be suitable as a therapeutic agent against autoimmune diseases.⁸

Herbal treatment of allergic rhinitis and neurodermatitis

Allergic rhinitis is the most common chronic and allergic disease. Nigella sativa is traditionally used in this area and promises relief due to its anti-allergic, anti-inflammatory and antioxidant properties. Clinical research shows that taking capsules containing 0.5 ml of black seed oil daily for two weeks reduces symptoms such as itching, stuffy or runny nose and sneezing in adults with allergic rhinitis.⁷ Other preliminary clinical trials showed that taking 40-80 mg of black seed oil per kg body weight daily for 4 to 8 weeks improved the self-rated symptoms of allergic rhinitis in 81% of patients (placebo: 45% of patients).⁴ Black seed also shows potential as an adjuvant to specific immunotherapy. In a controlled study with house dust mite allergy patients, the supplementary allergen-specific immunotherapy with black cumin was investigated. Taking an additional 2 g of black cumin seed daily further increased phagocytotic and intracellular destruction activities by polymorphonuclear leukocytes. The CD8 counts of patients receiving specific immunotherapy with supplementation increased significantly in contrast to patients receiving specific immunotherapy alone. The authors see the cause for the symptom improvement in allergic rhinitis in the antihistaminergic effect of black cumin already confirmed by in vitro experiments.⁹ Kalus et al. studied neurodermatitis patients. The results showed that in 50 % of the treated patients the subjectively assessed symptoms of atopic dermatitis improved compared to baseline. Black cumin oil is therefore suitable as an effective complementary phytotherapeutic agent in the treatment of allergic diseases.4 Animal studies suggest that the reason for this also lies in the immunomodulatory properties of black cumin. The active ingredient thymoquinone appears to modulate the Th1/Th2 immune balance; it reduces the infiltration of inflammatory cells from the blood, the expression levels of IL-4, IL-5 and IFN-μ and also the IgE levels.¹⁰

The influence of Nigella sativa on the control of asthma

The Global Asthma Initiative defines asthma as a heterogeneous disease usually characterised by chronic inflammation of the airways. It is identified by a history of respiratory symptoms such as wheezing, shortness of breath, chest tightness and cough, which vary over time and in intensity, along with variable limitation of expiratory airflow. The Global Asthma Report 2014 considers asthma to be an epidemic disease, likely affecting 334 million people worldwide, making it a global priority health issue.¹¹ Asthma is triggered by multiple interactions between inflammatory cells and mediators. At least 27 cytokines and 18 chemokines play a role in the pathophysiology of asthma, with Th2 cytokines (interleukin(IL)-4, IL-5 and IL-13) and Th1 cytokine interferon-gamma being the most important. Preclinical studies with black seed preparations showed bronchodilator, antihistaminergic, anti-inflammatory, leukotriene inhibitory and immunomodulatory effects in animal or cell models of asthma.¹¹ These effects of black seed were confirmed in a randomised controlled human trial. 80 asthma patients were given 0.5 g of black seed oil or a placebo twice daily for four weeks. Black seed oil supplementation increased asthma control with a trend towards improved lung function. This was associated with a remarkable normalisation of elevated peripheral blood eosinophils, which are an important biomarker in asthma trials.¹² Black seed also proved effective as a supplement to standard inhalation therapy. Administered as capsules with ground seeds in doses of 1 or 2 g daily, the phytotherapeutic improved some parameters of pulmonary function and inflammation in partially controlled asthma. The improvement in pulmonary function tests suggests a bronchodilator effect of Nigella sativa. This study was also the first to show that administration of 1 g black cumin daily reduced fractional exhaled nitric oxide, indicator of the inflammatory response underlying the pathogenesis of bronchial asthma. Unfortunately, no values are available for asthma markers in sputum or bronchial lavage.¹³ Boskabady et al. investigated the bronchodilator effects of black seed on asthmatics treated with cortisone spray, salbutamol inhalation, atrovent, fluticasone or euphylline. In this open-label study, the effect of 50 or 100 mg of a cooked extract of black seed per kg body weight was compared with euphylline and salbutamol. After taking both doses of extract, lung function scores improved, although the improvements from the black seed active ingredient were inferior to those from euphylline and salbutamol. The study nevertheless suggests that black seed has potent antiasthmatic effects.¹⁴ This study was preceded by a randomised controlled trial of 29 asthmatics who received either black seed extract or a placebo for three months. With black seed treatment, asthma symptoms improved significantly, the frequency of symptoms per week and spastic breath were reduced, and lung function scores increased significantly. In addition, the patients needed less of the above-mentioned antiasthmatics.⁵

The cardiometabolic protective potential of Nigella sativa

The level of cardiometabolic disorders has reached epidemic proportions throughout the world. Nigella sativa has been recommended for medicinal purposes in this therapeutic setting for many centuries, especially due to its antioxidant, anti-inflammatory, hypoglycaemic, antihypertensive and antihyperlipidaemic properties.¹⁵ Hallajzadeh et al. evaluated the effects of black cumin supplements on glycaemic control, lipid profiles and biomarkers of inflammatory and oxidative stress using a meta-analysis of 50 recent randomised controlled trials with a total of 3679 participants. This analysis confirmed the blood lipid-lowering effect of black cumin mediated through various ingredient mechanisms. Black cumin significantly reduces total, VLDL, LDL cholesterol and triglycerides. In addition to elevated blood lipids, glucose homeostasis also plays a role in the development of atherosclerosis - here, too, black cumin has a regulating effect. Thus, a significant reducing effect on fasting glucose and HbA1C levels was observed, which allows a conclusion to be drawn about the average blood glucose level and is therefore an important diabetes marker. Through its glucose-lowering properties, black cumin also indirectly reduces the production of free radicals and strengthens the antioxidant system. The meta-analysis thus highlighted the positive effects of black cumin on fasting glucose, HbA1c, triglycerides, total, VLDL and LDL cholesterol levels, thus underlining the importance of black cumin as a natural and proven remedy with cardiovascular protective potential.² In a randomised placebo-controlled trial in mildly overweight postmenopausal women, levels of total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol and blood glucose improved significantly after two months of supplementation. This suggests that black cumin is beneficial for the prevention and treatment of metabolic syndrome, especially during menopause when the risk for changes increases.^{16, 17} Also, in studies of patients with metabolic syndrome on standard therapy (atorvastatin, metformin), 6 weeks of supplementation with 5 ml of Nigella sativa oil per day significantly improved LDL and HDL levels and fasting blood glucose compared to the control group.^{15, 18}

Blood pressure lowering effect of black cumin

The active components of Nigella sativa are thymoquinone, dithymoquinone, thymohydroquinone, thymol, carvacrol, anethole and terpinen-4-ol. The blood pressure-lowering effect is presumably mainly due to the essential oils contained.¹⁹ However, other components, such as soluble dietary fibre, flavonoids and the high content of unsaturated fatty acids (linoleic, oleic and arachidonic acid), could also influence hypertension control. While no mechanisms of hypertension control by Nigella sativa are known, a cardiac sedative effect, a diuretic effect or a calcium channel blocking function are suspected.20 A systematic review and meta-analysis of clinical trial results showed that taking up to 3 g of black seed oil or 0.5-2 g of black seed extract daily for a period of 4-12 weeks reduced systolic (SBD) and diastolic blood pressure (DBD) by about 3 mmHg in subjects with or without hypertension.²⁰ A study in patients with or without hypertension found that taking 2.5 ml of black seed oil twice daily for 8 weeks reduced SBD by about 11 mmHg and DBD by about 10 mmHg.²¹ An 8-week randomised placebo-controlled trial investigated the efficacy of black seed in mild hypertension. The studies showed a clear decrease in SBD and DBD. As a concomitant effect, total cholesterol and LDL cholesterol also decreased. It is assumed that the blood pressure-lowering effect of the essential oil in black cumin is due to its antioxidant properties,²² which were confirmed by thin-layer chromatography.¹⁹ Previous studies have already established a connection between the administration of antioxidants or their plasma levels and hypertension, but also atherosclerosis and strokes.²² In older people with high blood pressure, the lack of elasticity of the arteries is a characteristic part of the pathogenesis. Since Nigella sativa also increases the production of nitrite oxide, which counteracts the rigidity of the arteries, the use of the extract was also studied in elderly patients (average age: 72 years). In this study, the SBD and DBD reduction was not significant, although there was a clinically relevant tendency towards reduced SBD. A successful reduction of blood pressure in elderly patients could not be proven. Reasons for this could be, on the one hand, the already very high arterial stiffness and, on the other hand, the high proportion of women in the group studied. Elevated blood pressure is more difficult to treat in older women than in older men. The study period of 28 days was short; further studies with older patients over a longer period of time are needed here.²³

Side-effect-free diabetes management with the help of Nigella sativa

The majority of clinical research shows that taking at least 1 g of black seed oil daily improves fasting blood glucose levels. One clinical trial showed that taking this dose of black seed oil for eight weeks reduced fasting blood glucose, triglyceride and low-density lipoprotein (LDL) cholesterol levels compared to placebo.²⁴ Other research showed that taking 1350 mg of black seed oil daily for 12 weeks reduced fasting blood glucose by about 14 mg/dl and HbA1c by 0.3% in newly diagnosed type II diabetics. Administration of black seed oil, unlike metformin, was tolerable and free of side effects, but taking 2000 mg of metformin daily was more effective in terms of diabetes management.²⁵ Badar et al. conducted a one-year study in which black seed extract was administered to type 2 diabetics. After a daily intake of 2 g of black cumin seed extract, a significant decrease in SBD and DBD, mean arterial blood pressure and also heart rate were observed, in addition to significantly positive effects on blood lipid levels. In this study, too, the positive effect was mainly explained by the potential of the plant seeds to counteract the increased oxidative stress, which plays a role in lipometabolic disorders and also hypertension. From the results it is concluded that black cumin seeds are suitable as a therapy supplement, especially in combination with other anti-atherogenic and blood pressure-lowering drugs for the treatment of diabetic complications.²⁶

Reduction of risk factors in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is on the rise and already affects about 25% of the world's population. Starting with an accumulation of triglycerides in the liver (steatosis), NAFLD can lead to hepatic and cardiovascular morbidity and mortality. NAFLD is strongly associated with metabolic syndrome factors, particularly insulin resistance. A three-month administration of 65 ml of black seed oil daily increased HDL cholesterol levels and reduced levels of liver function enzymes, LDL cholesterol and triglycerides in a preliminary clinical study. There was also a moderate improvement in the degree of steatosis. Black cumin oil appears to reverse hepatic damage, protect the liver of NAFLD patients and also influence hepatic lipid and triglyceride metabolism. Here, a choleretic effect of the plant could come into play,²⁷ but also anti-inflammatory and antioxidant properties, which emanate especially from the ingredient thymoquinone, play a role. Nigella sativa is thus suitable as an adjuvant for reducing systemic inflammation and reduces fasting blood glucose levels, blood lipid levels, liver enzymes and inflammatory factors (hs-CRP, TNF-α and IL-6) in NAFLD patients when taken at 1 g per day for 8 weeks.²⁸

Black cumin oil for the supportive treatment of overweight

The epidemic of overweight and obesity is a major health challenge worldwide. Meta-analyses of preliminary clinical trials with a total of 875 patients show that daily intake of 3-5 g of black seed oil for up to 13 weeks reduces body weight by about 2 kg and body mass index (BMI) by 0.85-1.2 kg/m2.^{29, 30} One of these studies showed that daily intake of 3 g of black seed oil for eight weeks in addition to a calorie-restricted diet reduced the weight of obese women by 5 kg, BMI by 1 kg/m2 and waist circumference by 7 cm. Compared to women on a low-calorie diet alone, the reduction in body weight and waist circumference, but not BMI, was statistically significant. Obesity is typically associated with increased risk factors for cardiovascular disease. Comparison of biochemical parameters showed a significant decrease in triglyceride and very-low-density lipoprotein (VLDL) levels in the black seed oil group. Black seed oil in combination with a low-calorie diet can thus reduce cardiometabolic risk factors in obese women.³¹ In obese men who received 1.5 g of black seed twice daily for a period of three months, supplementation appeared to eliminate most subjective complaints. Symptoms such as loss of libido (84% of men), forgetfulness (89%), large appetite (73%), pain and arthralgia (74%), insomnia (54%) and laziness (74%) disappeared completely, with no changes in the placebo group. In addition, body weight and waist circumference decreased statistically significantly and other health biomarkers improved, albeit to a lesser extent. This may be indicative of metabolic recovery in men with central obesity.³²

Immunomodulating and pain-inhibiting effect in rheumatoid arthritis

Rheumatoid arthritis (RA) is a debilitating autoimmune disease characterised by significant pain, progressive joint discomfort and associated functional impairment, affecting 0.5-1% of adults worldwide. The cause of the disease is unknown, but immunological and nutritional factors are thought to play a role, as well as oxidative stress, hormonal agents, genetics and infectious diseases. Various immune cells are involved in pathogenesis, including monocytes, macrophages, and T and B lymphocytes, resulting in increased production of inflammatory cytokines such as TNF-α, interleukin(IL)-1β and IL-6. Some of these cells lead to the destruction of synovium, cartilage and bone. TNF-α stimulates the nuclear factor-kappa B(NF-κB) signalling pathway, which leads to the production of inflammatory cytokines that play an important role in RA.³³ In addition, there is evidence that CD4+, CD8+ and CD4+-CD25+ T lymphocytes play a role in inducing or fighting rheumatoid arthritis. This was investigated in a randomised double-blind study in 2016. For two months, 43 women with RA were given either 500 mg of black seed oil twice daily or a placebo. Analysis by flow cytometry showed that there was a decrease in CD8+ T cells and an increase in CD4+-CD25+ T cells and the ratio of CD4+ to CD8+ under black seed oil treatment. In this group, there was a negative correlation between CD8+ and CD4+-CD25+ T cells and a positive correlation between CD4+-CD25+ T cells and the CD4+ to CD8+ ratio, demonstrating an immunomodulatory effect of Nigella sativa.³⁴ CD4+- have a protective effect in RA, while CD4+-CD25+ T cells suppress RA through IL-2-dependent mechanisms.³⁵ Treatment also significantly lowered serum levels of high-sensitivity C-reactive protein and disease activity score (DAS-28) and resulted in a reduced number of swollen joints compared to the baseline and placebo groups. This study supports the potential relevance of Nigella sativa in the clinical treatment of RA by modulating T-lymphocytes.³⁴ In a placebo-controlled study, 40 women with RA already treated with DMARDs (disease-modifying anti-rheumatic drugs) received 500 mg of black seed oil twice daily for one month. Again, the DAS-28 score decreased significantly after taking Nigella sativa capsules compared to the placebo, as did the symptoms of RA, such as morning stiffness and swollen joints. Nigella sativa may be considered a cost-effective adjuvant biotherapeutic during DMARD therapy for RA.³⁶ A review summarised three human clinical trials with the results of animal studies and concluded that black seed oil, particularly its thymoquinone content, has anti-inflammatory and analgesic effects through several pathways. The analgesic effect of Nigella sativa oil is attributed to the suppression of nociceptive systems or inflammatory mediators, and the opioid system is also involved in pain inhibition.³⁵

Adjuvant in the eradication of Helicobacter pylori

Standard therapies used to eradicate the stomach-colonising bacterium Helicobacter pylori are based on antibiotics. However, the resistance of H. pylori to antibiotics is increasing and it is necessary to find new effective agents. This is because only successful treatment of the infection will lead to a decrease in H. pylori-associated diseases, such as chronic gastritis and stomach ulcers. Nigella sativa seeds demonstrated anti-Helicobacter activity in vitro.³⁷ Supplementing standard therapies with black seed preparations appears to increase the likelihood of successful H. pylori eradication. In clinical research, H. pylori eradication was successful in 88% of patients who received 8 weeks of quadruple therapy with metronidazole, amoxicillin, bismuth subcitrate and omeprazole combined with 2 g of black seed powder daily, compared with 55% of patients who underwent quadruple therapy alone. Patients' quality of life also improved.³⁸ Salem et al. also showed that taking 2 g of black seed powder daily for 4 weeks, combined with omeprazole to eradicate H. pylori was similarly effective to the standard 1-week triple therapy of clarithromycin, amoxicillin and omeprazole. However, this effect was only seen at the 2 g dose of black seed powder, but 1 and 3 g still produced similar eradication rates as a single antibiotic. Combining black seed preparations with the proven antibiotic combinations could result in a more efficient therapy that is safe and cost-effective.³⁷

Traditional remedy for infertility

As the seeds of Nigella sativa are used in many ways in traditional medicine, including against infertility, their effect on men with below-average sperm quality is quite interesting. Clinical research shows that taking 5 ml of black seed oil daily for 2 months improves sperm count in infertile men by 40%, sperm morphology by 32% and sperm motility by 13%, as well as semen volume, pH and the proportion of round cells.³⁹

Strengthening of the hepatic antioxidant protection systems

In addition to a general increase in antioxidant status, black cumin oil particularly strengthens the endogenous antioxidant protection systems of the liver. Both the lipid peroxidation of hepatocyte membranes and the oxidation of liver enzymes can be reduced by the additional supplementation with black cumin oil.⁴⁰ Since the liver, as a central detoxification organ, is exposed to a special oxidative load by liver toxins, an efficient increase of the preventive protective functions takes place through the radical scavenging mechanisms. This is particularly important when taking medication. Black cumin oil also shows neuroprotective properties. Here, too, the prevention of lipid peroxidations at the membranes is assumed to be the cause. In studies, an anti-epileptic effect was observed in this context.⁴¹

The anticarcinogenic effect of the Nigella sativa ingredients

The active ingredients alpha-hederine and thymoquinone are considered potent cytotoxic and apoptotic substances with regard to tumour cells.² Thymoquinone in particular seems to be able to stop the growth of colon cancer cells and is used as an adjuvant therapeutic for colorectal cancer.42, 43 Scientific studies on animal models indicate an anticarcinogenic effect also in breast cancer.44 After Nigella sativa administration, the values for oxidative stress, the tumour-specific endocrine markers as well as the parameters for carcinogenesis were significantly improved.⁴⁵ The cytotoxic properties have also been proven in various studies.⁴⁶

Indications

Effect	Indication	Dosage
Physiological effects at low nutrient intake	Adjuvant therapy for asthma, hay fever, dust and contact allergies	3 g/d
	Complementary therapy for hypertension (high blood pressure), diabetes and metabolic syndrome	3 g/d
	To reduce the risk factors in fertility disorders	3 g/d
	For use in autoimmune diseases such as rheumatoid arthritis	3 g/d
	For the supportive treatment of overweight	3 g/d
	To accompany the eradication of Helicobacter pylori with medication	3 g/d
	Complementary for infertility	3 g/d
	Complementary therapy to strengthen antioxidative protective systems, especially in the  Liver during drug therapy	3 g/d
	Preventive and complementary therapy for Tumors	3 g/d

Administration

General mode of administration
When	Black seed oil should be taken with meals. Notes: Nigella sativa belongs to the botanical family of Ranunculaceae and should not be used in the case of a known allergy to any flower of this family.
Side effects
No side effects are known to date.
Contraindications
Due to the fact that Nigella sativa belongs to the botanical family of Ranunculaceae (buttercups), it should not be used in the case of a known allergy.

Interactions

Drug interactions
None	No interactions are known to date.
Nutrient interactions
None	No interactions are known to date.

References

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² Rooney, S., Ryan, M. F. 2005. Effects of alpha-hederin and thymoquinone, constituents of Nigella sativa, on human cancer cell lines. Anticancer Res. 25(B):2199–204.
³ Hallajzadeh, J. et al. 2020. Effects of Nigella sativa on glycemic control, lipid profiles, and biomarkers of inflammatory and oxidative stress: A systematic review and meta-analysis of randomized controlled clinical trials. Phytother Res. 34(10):2586–608.
⁴ Kalus, U. et al. 2003. Effect of Nigella sativa (black seed) on subjective feeling in patients with allergic diseases. Phytother Res. 17(19):1209–14
⁵ Boskabady, M. H. et al. 2007. The possible prophylactic effect of Nigella sativa seed extract in asthmatic patients. Fundam Clin Pharmacol. 21(5):559–66.
⁶ Ipci, K. et al. 2016. Alternative products to treat allergic rhinitis and alternative routes for allergy immunotherapy. Am J Rhinol Allergy. 30(5):8–10.
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⁸Salem, M. L. 2005. Immunomodulatory and therapeutic properties of the Nigella sativa L. seed. Int Immunopharmacol. 5(13–14):1749–70.
⁹Işık, H. et al. 2010. Potential Adjuvant Effects of Nigella sativa Seeds to Improve Specific Immunotherapy in Allergic Rhinitis Patients. Med Princ Pract. 19(3):206–11.
¹⁰ Aslam, H. et al. 2018. Immunomodulatory effect of thymoquinone on atopic dermatitis. Mol Immunol. 101:276–83.
¹¹ Koshak, A. et al. 2017. Medicinal benefits of Nigella sativa in bronchial asthma: A literature review. Saudi Pharm J. 25(8):1130–6.
¹²Koshak, A. et al. 2017. Nigella sativa Supplementation Improves Asthma Control and Biomarkers: A Randomized, Double-Blind, Placebo-Controlled
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¹³ Salem, A. M. et al. 2017. Effect of Nigella sativa supplementation on lung function and inflammatory mediators in partly controlled asthma: a randomized controlled trial. Ann Saudi Med. 37(1):64–71.
¹⁴ Boskabady, M. H. et al. 2010. Antiasthmatic effect of Nigella sativa in airways of asthmatic patients. Phytomedicine. 17(10):707–13.
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²¹Huseini, H. F. et al. 2013. Blood Pressure Lowering Effect of Nigella sativa L. Seed Oil in Healthy Volunteers: A Randomized, Double-Blind, Placebocontrolled Clinical Trial. Phytother Res. 27(12):1849–53.
²² Dehkordi, F. R., Kamkhah, A. F. 2008. Antihypertensive effect of Nigella sativa seed extract in patients with mild hypertension. Fundam Clin Pharmacol. 22(4):447–52.
²³ Rizka, A. et al. 2017. Effect of Nigella sativa Seed Extract for Hypertension in Elderly: a Double-blind, Randomized Controlled Trial. Acta Med Indones. 49(4):307–13.
²⁴ Kooshki, A. et al. 2020. Effect of Nigella sativa oil supplement on risk factors for cardiovascular diseases in patients with type 2 diabetes mellitus. Phytother Res. 34(19):2706–11.
²⁵ Moustafa, H. A. M. et al. 2019. Effect of Nigella Sativa oil versus metformin on glycemic control and biochemical parameters of newly diagnosed type 2 diabetes mellitus patients. Endocrine. 65(2):286–94.
²⁶ Khonche, A. et al. 2019. Standardized Nigella sativa seed oil ameliorates hepatic steatosis, aminotransferase and lipid levels in non-alcoholic fatty liver disease: A randomized, double-blind and placebo-controlled clinical trial. J Ethnopharmacol. 234:106–11.
²⁷ Khonche, A. et al. 2019. Standardized Nigella sativa seed oil ameliorates hepatic steatosis, aminotransferase and lipid levels in non-alcoholic fatty liver disease: A randomized, double-blind and placebo-controlled clinical trial. J Ethnopharmacol. 234:106–11.
²⁸ Rashidmayvan, M. et al. 2019. The effect of Nigella sativa oil on serum levels of inflammatory markers, liver enzymes, lipid profile, insulin and fasting blood sugar in patients with non-alcoholic fatty liver. J Diabetes Metab Disord. 18(2):453–9.
²⁹ Mousavi, S. M. et al. 2018. Effect of Nigella sativa supplementation on obesity indices: A systematic review and meta-analysis of randomized controlled trials. Complement Ther Med. 38:48–57.
³⁰ Namazi, N. et al. 2018. The effects of Nigella sativa L. on obesity: A systematic review and meta-analysis. J Ethnopharmacol. 219:173–81.
³¹ Mahdavi, R. et al. 2015. Effects of Nigella sativa oil with a low-calorie diet on cardiometabolic risk factors in obese women: a randomized controlled clinical trial. Food Funct. 6(6):2041–8.
³² Datau, E. A. et al. 2010. Efficacy of Nigella Sativa on Serum Free Testosterone and Metabolic Disturbances in Central Obese Male. Acta Med Indones. 42(3):130–4.
³³ Hadi, V. et al. 2016. Effects of Nigella sativa oil extract on inflammatory cytokine response and oxidative stress status in patients with rheumatoid arthritis: a randomized, double-blind, placebo-controlled clinical trial. Avicenna J Phytomed. 6(1):34–43.
³⁴ Kheirouri, S. et al. 2016. Immunomodulatory Effect of Nigella sativa Oil on T Lymphocytes in Patients with Rheumatoid Arthritis. Immunol Invest. 45(4):271–83.
³⁵ Mahboubi, M. et al. 2018. Nigella sativa fixed oil as alternative treatment in management of pain in arthritis rheumatoid. Phytomedicine. 46:69–77.
³⁶ Gheita, T. A., Kenawy, S. A. 2012. Effectiveness of Nigella sativa oil in the management of rheumatoid arthritis patients: a placebo controlled study. Phytother Res. 26(8):1246–8.
³⁷ Salem, E. M. et al. 2010. Comparative study of Nigella Sativa and triple therapy in eradication of Helicobacter Pylori in patients with non-ulcer dyspepsia. Saudi J Gastroenterol. 16(3):207–14.
³⁸ Alizadeh-Naini, M. et al. 2020. The beneficial health effects of Nigella sativa on Helicobacter pylori eradication, dyspepsia symptoms, and quality of life in infected patients: A pilot study. Phytother Res. 34(6):1367–76.
³⁹ Kolahdooz, M. et al. 2014. Effects of Nigella sativa L. seed oil on abnormal semen quality in infertile men: a randomized, double-blind, placebocontrolled clinical trial. Phytomedicine. 21(6):901–5.
⁴⁰ Kanter, M. et al. 2003. Effects of Nigella sativa L. and Urtica dioica L. on lipid peroxidation, antioxidant enzyme systems and some liver enzymes in CC14-treated rats. J Vet Med A Physiol Pathol Clin Med. 50(5):264–8.
⁴¹ Ilhan, A. et al. 2005. Antiepileptogenic and antioxidant effects of Nigella sativa oil against pentylenetetrazol induced kindling in mice. Neuropharmacology. 49(4):456–464.
⁴² Kundu, J. et al. 2014. Thymoquinone induces apoptosis in human colon cancer HCT116 cells through inactivation of STAT3 by blocking JAK2- and Src mediated phosphorylation of EGF receptor tyrosine kinase. Oncol Rep. 32:821–828.‘
⁴³ Gali-Muhtasib, H. et al. 2008. Thymoquinone reduces mouse colon tumor cell invasion and inhibits tumor growth in murine colon cancer models. J Cell Mol Med. 12(1):330–42.13.
⁴⁴ Woo, C. C. et al. 2013. Thymoquinone Inhibits Tumor Growth and Induces Apoptosis in a Breast Cancer Xenograft Mouse Model: The Role of p38 MAPK and ROS. PLoS One. 8(10):e75356.
⁴⁵ El-Aziz, M. A. A. et al. 2005. The biochemical and morphological alterations following administration of melatonin, retinoic acid and Nigella sativa in mammary carcinoma: an animal model. Int J Exp Pathol. 86(6):383–96.
⁴⁶ Islam, S. N. et al. 2004. Immunosuppressive and cytotoxic properties of Nigella sativa. Phytother Res. 18(5):395–8.

References Interactions
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