Review of Black Cumin for Metabolic Disorders

Black cumin (Nigella sativa, Ranunculaceae) seed is popular in the Middle East and Southeast Asia for treating diabetes, dyslipidemia, hypertension, and obesity. However, clinical evidence is inconclusive. The purpose of this systematic review was to evaluate the clinical and biochemical effects of black cumin on lipid profiles, glycemic factors, blood pressure, and anthropometric indices (weight, body mass index [BMI], and waist circumference), all of which are parameters of metabolic syndrome.

The following databases were searched from inception through June 2014: PubMed, Google Scholar, Thomson Reuters Web of Science, and Cochrane. The following medical subject headings (MeSH) and title/abstract (tiab) search terms were used: (“Nigella sativa” [MeSH] OR “black seed” [tiab] OR “black cumin” [tiab] OR “Kalonji” [tiab]) AND “Triglycerides” [MeSH] OR “Cholesterol” [MeSH] OR “Lipoproteins, LDL” [MeSH] OR “Lipoproteins, HDL” [MeSH] OR “Blood glucose” [MeSH] OR “Hemoglobin A, Glycosylated” [MeSH] OR “Blood pressure” [MeSH] OR “Body mass index” [MeSH] OR “Waist circumference” [MeSH]). The inclusion criteria were (1) published in English, (2) the effect of black cumin on clinical or biochemical parameters, and (3) clinical trial. The exclusion criteria were (1) animal studies, (2) review studies, (3) the effect of black cumin on unrelated blood or clinical parameters, (4) the effect of black cumin combined with other plants or exercise, and (5) duplicated studies.

A total of 515 articles were located, and 18 studies (with a total of 1531 subjects) met the inclusion/exclusion criteria. The studies were highly heterogeneous: five studies were randomized, double-blind, controlled studies; five studies had no control group, and eight studies were randomized controlled studies. Included patients were aged 18-65 years and had diabetes (n = 5 studies), metabolic syndrome (n = 7 studies), hyperlipidemia (n = 4 studies), hypertension/coronary disease (n = 2 studies), obesity (n = 1 study), or were healthy subjects (n = 4 studies). All treatments were oral and doses ranged from 200 mg/day to 5 g/day of seed extract (n = 2 studies), seed oil (n = 8 studies), or seed powder (n = 13 studies). Treatment duration ranged from two weeks to six months.

Table 1 summarizes the study findings. The authors note significant findings; however, they do not report whether the changes are compared with baseline or control. In Table 1, the column titled “overall effect” indicates which parameters had more evidence in favor of a significant improvement.

Table 1: Summary of Number of Studies with Significant Improvements in Measured Parameters

Number of Studies
Parameters Significant improvement No significant effect Overall effect (Yes/No)
Triglycerides 7 10 No
Total cholesterol 10 4 Yes
Low-density lipoprotein (LDL) cholesterol 11 3 Yes
High-density lipoprotein (HDL) cholesterol 6 10 No
Fasting blood sugar 13 3 Yes
Glycosylated hemoglobin 4 Yes
Blood pressure 4 5 No
Weight 2 6 No
BMI 2 6 No
Waist circumference 1 5 No

Based on the number of studies demonstrating a significant improvement, the evidence weighs more in favor of black cumin improving total cholesterol, LDL, fasting blood sugar, and glycosylated hemoglobin. Evidence does not support an effect of black cumin on blood pressure or anthropometric indices. A total of 10 studies evaluated safety. Two studies that treated subjects with 5 mL/day black cumin seed oil reported mild nausea that resolved after one week of treatment. Eight studies measured liver and kidney function and reported no adverse effects.

The authors conclude that black cumin should be “a complementary treatment protocol for many diseases, especially metabolic disorders.” However, even though the evidence leans more favorably in the direction of a benefit for some parameters, the heterogeneity of the studies must be taken into consideration. It would have been advantageous if the researchers conducted a meta-analysis to provide more scientific rigor to their analysis and conclusions. Recommendations for the effective dose or preparation cannot be gleaned from this analysis. More research is needed if black cumin is to be recommended as a treatment for patients with symptoms of metabolic syndrome.

Resource:

Mohtashami A, Entezari MH. Effects of Nigella sativa supplementation on blood parameters and anthropometric indices in adults: A systematic review of clinical trials. J Res Med Sci. 2016;21:3. doi: 10.4103/1735-1995.175154.

 

Black Cumin Does Not Decrease Levels of Oxidative Stress Markers in Women with Rheumatoid Arthritis

  • Black Cumin (Nigella sativa, Ranunculaceae)
  • Rheumatoid Arthritis
  • Inflammation
  • Oxidative Stress

Rheumatoid arthritis (RA) is a progressive, inflammatory autoimmune disease that causes pain, swelling, stiffness, and deformity of the joints. It is thought that the pathogenesis of RA involves chronic oxidative stress and chronic inflammation. Hence, treatments that have anti-inflammatory and antioxidant effects may be beneficial. Black cumin (Nigella sativa, Ranunculaceae) seed oil is used in Iranian traditional medicine. It has been shown to have anti-inflammatory and antioxidant activity in animal models of inflammation by suppressing the elevated levels of pro-inflammatory cytokines and pro-oxidants. The purpose of this randomized, double-blind, placebo-controlled study was to evaluate the effects of black cumin seed oil on the concentration of selected inflammatory cytokines and oxidative stress markers in women with RA.

Patients (n = 42, aged 20-50 years) were recruited from Sheykholrayis Outpatient Clinic, affiliated with Tabriz University of Medical Sciences, in Tabriz, Iran, from May 2012 to November 2013. Included patients had mild to moderate RA according to the 2010 American College of Rheumatology/European League Against Rheumatism (ACR-EULAR) criteria; were being treated with methotrexate, hydroxychloroquine, or prednisolone; were not receiving any non-steroidal anti-inflammatory drugs or cytokine inhibitors for ≥ 2 months prior to study entry; and had body mass index (BMI) < 40. Excluded patients were pregnant or lactating; were taking hormone therapy or oral contraceptives; had metabolic disorders such as diabetes mellitus, lactose intolerance, Cushing’s syndrome, or thyroid dysfunction; had kidney or liver disease; had chronic inflammatory disease including inflammatory bowel diseases; had a history of taking antioxidant or anti-inflammatory supplements 4 weeks prior to the study; or had a history of being on weight-reduction diets or smoking.

Patients received placebo (paraffin) or 1000 mg/day black cumin seed oil capsules for 8 weeks. Both placebo and black cumin seed oil soft gels were formulated, developed, and produced by Barij Asans of Kashan (Barij Essence Pharmaceutical Company); Kashan, Iran. The authors do not describe the composition or concentration of the black cumin seed oil. Physical activity level and psychological stress were assessed via International Physical Activity Questionnaire and State-Trait Anxiety Inventory Form Y (STAI-Y), respectively. Dietary intake was evaluated using a 3-day dietary record before and after the intervention, and the data was analyzed using Nutritionist IV software. Disease activity was monitored via the Disease Activity Score Calculator for Rheumatoid Arthritis. Fasting blood was collected at baseline and after 8 weeks of treatment. Serum levels of the inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-10 (IL-10) and the oxidative stress indicators total antioxidant capacity (TAC), superoxide dismutase (SOD), catalase (CAT), and nitric oxide (NO) were measured.

Groups were similar at baseline. Fifty women were enrolled in the study and 42 completed the study. Of the 25 women in the placebo group, 7 dropped out for reasons not related to the intervention and 2 were excluded from the analysis due to infection or medication change, leaving 16 patients in the per-protocol analysis. In the black cumin group, 1 patient dropped out for reasons not related to the intervention and 1 was excluded due to the medication change, leaving 23 patients in the per-protocol analysis. The author’s power calculation indicated that 18 patients in each group were required for statistical significance. Compared with baseline, at 8 weeks, there were no significant changes in BMI, STAI-Y, physical activity, micronutrient intake, energy intake, or macronutrient intake.

At study end, disease activity score was significantly decreased in the black cumin group compared with baseline (P < 0.05), while there was no significant change in the placebo group (data not shown; the between-group difference was not reported). The black cumin group had a significant increase in IL-10 (P < 0.01) and significant decreases in malondialdehyde (MDA; P = 0.04) and NO (P = 0.01) compared to baseline; however, the difference between groups was not statistically significant. There were no significant effects on TNF-α, SOD, CAT, or TAC.

The authors conclude that black cumin “could improve inflammation and reduce oxidative stress in patients with RA … .” However, the data presented do not support their conclusion. Black cumin significantly increased the level of the inflammatory cytokine IL-10, indicating a pro-inflammation effect. Although black cumin decreased the levels of the oxidative stress markers MDA and NO compared to baseline, there was no significant difference in these parameters between the black cumin and placebo groups, and black cumin had no effect on the other 4 oxidative stress markers. Limitations of this study include the following: the size of the placebo group was too small to detect statistically significant treatment effects; relatively short study duration; lack of safety/adverse event and compliance reporting; and chemical composition and concentration of the black cumin seed oil was not reported. The authors declare no conflicts of interest; however, one of the authors *(Hosseini) is an employee of Barij Essence Pharmaceutical Company.

*Hadi V, Kheirouri S, Alizadeh M, Khabbazi A, Hosseini H. 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. 2016;6(1):34-43.

Potential Role of Nigella in Prevention and Control of Hypertension

  • Nigella (Black Cumin; Nigella sativa)
  • Hypertension
  • Oxidative Stress

Nigella (black cumin; Nigella sativa), also known by its Arabic name habat-ul sauda or habbatussauda, has been used for centuries medicinally and as a food spice throughout the Middle East, India, and Northern Africa. It is an annual flowering plant with pale blue flowers and has fruit with black, angular seeds. The seeds are used for treating diabetes, hypertension, hypercholesterolemia, inflammation, and gastrointestinal disorders. The purpose of this article was to review the literature evaluating the antihypertensive effect of nigella.

The seed oil is rich in polyphenols and tocopherols. The seeds contain 36-38% fixed oils (mainly fatty acids: linoleic [C18:2], oleic [C18:1], palmitic [C16:0], and stearic [C18:0] acids), 0.4-2.5% essential (volatile) oil, proteins, alkaloids, saponins, and 30-48% thymoquinone along with its derivatives dithymoquinone, thymohydroquinone, and thymol. Thymoquinone is the most pharmacologically active ingredient in abundance in the seeds.

The seed oil has strong antioxidant properties. In particular, thymoquinone is a potent superoxide radical scavenger which is as effective as superoxide dismutase (SOD) against superoxides generated either photochemically, biochemically or derived from calcium ionophore. Thymoquinone has a strong protective effect by decreasing oxidative stress through preserving glutathione and increasing the levels and activities of antioxidant enzymes like SOD and glutathione peroxidase.

Oxidative stress may play an important role in hypertension pathogenesis by enhancing sequestration of nitric oxide (NO) by reactive oxygen species (ROS), forming lipid peroxidation products, and depleting nitric oxide synthase (NOS) cofactor tetrahydrobiopterin. NO causes vasodilation that reduces peripheral resistance, thus decreasing blood pressure so its lower bioavailability may result in endothelial dysfunction. Also, oxidative stress may cause functional and structural damage in the molecules and cells of the vascular wall and blood vessels. Therefore, nigella may protect against hypertension via its antioxidant abilities. However, more research is needed to test this hypothesis.

Hypertension may be reduced by a cardiac depressant effect, calcium channel blockage, and a diuretic effect. Studies show that nigella volatile oil and thymoquinone decreased arterial blood pressure and heart rate in rats, which was mainly mediated centrally, either directly or indirectly, via serotoninergic and muscarinic receptors. Also in rats, the cardiac depressant effects of nigella may be mediated by nicotinic receptors. Overall, the cardiac depressant and hypotensive effects of nigella may be centrally mediated, involving the vasomotor center of the medulla and sympathetic outflow to the periphery. Thymol has been shown to dose-dependently reduce blood pressure by inhibiting calcium ion channels. When calcium channels are blocked, vasorelaxation increases. Kidney function is important for the control and pathogenesis of hypertension. Nigella may decrease blood pressure via a diuretic action; it increased urinary excretion of sodium, potassium, chloride, and urea. It also increased glomerular filtration rate and urinary and electrolyte output, independent of the renin-angiotensin-aldosterone system.

One study in patients with mild hypertension revealed that oral nigella seed extract of 100 mg/day or 200 mg/day for eight weeks significantly and dose-dependently reduced diastolic and systolic blood pressure compared with placebo and baseline (P<0.01 for all; except systolic blood pressure with 100 mg/day, P=0.03). There were also significant decreases in total cholesterol and low-density lipoprotein (LDL) cholesterol (P<0.01 for both), and no adverse effects.1

The authors conclude that nigella may have cardiovascular protective effects via a multitude of actions. They state that nigella has been used in traditional medicine with no reported adverse events. The authors only include one clinical study assessing the effect of nigella seed extract in patients with hypertension. A quick search of PubMed revealed that there are only two clinical trials available for this indication. More studies in humans are needed to confirm efficacy.

Leong X-F, Mustafa MR, Jaarin K. Nigella sativa and its protective role in oxidative stress and hypertension. Evid Based Complement Altern Med. 2013;2013:120732. doi: 10.1155/2013/120732.

Black Cumin (Nigella sativa, Ranunculaceae)

Clinical Efficacy of Black Cumin

Gholamnezhad Z, Havakhah S, Boskabady MH. Preclinical and clinical effects of Nigella sativa and its constituent, thymoquinone: a review. J Ethnopharmacol. June 2016;190:372-386.

Black cumin (Nigella sativa, Ranunculaceae) has been used traditionally and clinically to treat several diseases and conditions, including infertility, fever, cough, bronchitis, asthma, migraine, diabetes, rheumatism, and hypertension. The seeds reportedly have antidiabetic, anticancer, anti-inflammatory, immunomodulatory, antioxidant, antimicrobial, analgesic, spasmolytic, bronchodilatory, and hepatoprotective properties. Although black cumin has been the subject of many reviews, none of them have focused on its clinical effects. These authors sought to provide a comprehensive report of clinical studies on black cumin and some of its constituents. The beneficial effects of black cumin have been attributed to its prominent constituents such as nigellicine, nigellidine, thymoquinone (TQ), dithymoquinone, thymol, and carvacrol; most of its biological activities are related to its essential oil components, mainly TQ.1

The authors searched for studies in PubMed, Science Direct, Scopus, and Google Scholar that took place between 1979 and 2015, using the terms N. Sativa, its constituents, its clinical effects, and various disorders.

Inflammation is the main characteristic of many chronic and acute diseases. The authors listed ten studies (seven clinical studies and three in vitro studies) that reported on the anti-inflammatory and immunomodulatory effects of black cumin and its constituents. In a placebo-controlled, crossover study,2 the investigators examined the anti-inflammatory effect of black cumin oil in patients with rheumatoid arthritis. The 40 patients received placebo capsules twice daily for one month and then consumed black cumin seed oil capsules (500 mg twice daily) for one month. After treatment, white blood cell count, disease activity score, the number of swollen joints, and duration of morning stiffness significantly decreased compared with baseline and with the placebo intervention. However, the authors of the review still suggest “more RCT [randomized, controlled trials] and N. Sativa supplementation is needed for the plant to be used as an inexpensive potential adjuvant biological therapy in inflammatory disorders.”

The effect of black cumin oil was compared with that of fish oil on vitiligo (an autoimmune skin disorder) lesions in a well-designed, randomized, double-blind clinical trial.3 Fifty-two patients were divided into two equal groups and applied oil twice daily on their lesions for six months. Both oils reduced the size of the lesions, but black cumin oil was more effective than fish oil. No significant adverse effects were reported. Because of the study’s limitations, including uncontrollable factors such as patient nutrition, which could influence skin lesions, the results cannot be generalized.

In well-designed in vitro studies, the lipid-soluble components of black cumin potentiated T-cell-mediated immunity and its water-soluble components affected B-cell-mediated immunity.

“All these studies showed that both lipid- and water-soluble fractions of N. Sativa are potent and safe immunomodulatory agents and could be recommended as prophylactic and therapeutic adjuvants in immune system diseases,” write the review authors.

Studies of the effects of black cumin essential oil against various bacteria resistant to a number of antibiotics were identified. The oil’s potent dose-dependent antibacterial activity was more pronounced against Gram-positive than Gram-negative bacteria. In a clinical study,4 the effects of ethanolic extracts of black cumin, ginger (Zingiber officinale, Zingiberaceae), and their mixture were evaluated in patients with hepatitis C. The extracts of black cumin seed and ginger decreased the viral load and altered liver function in those patients. Noting that the identified studies demonstrated that black cumin seed extract and oil are potent antimicrobial agents, the review authors state, “Isolation and the formulation of new antimicrobial components from this herb should be carried out in the future, and more clinical trials should be designated before marketing.”

Antitumor effects of TQ and ethanolic and aqueous black cumin extracts were shown in eight listed in vitro studies. Cytotoxic and apoptotic effects on human cell lines, including lung cancer, breast cancer, renal adenocarcinoma, colon cancer, osteosarcoma, and cervical squamous carcinoma, were observed; “however, more clinical trials are needed to recommend N. Sativa derivatives as potential anticancer products,” note the authors.

The effects of black cumin on metabolic disorders (including diabetes mellitus, hyperlipidemia, and metabolic syndrome) and on renal health were evaluated in 15 listed studies. In patients with type 2 diabetes mellitus, improvements were seen in fasting blood glucose, insulin resistance, glycosylated hemoglobin, and two-hour postprandial blood glucose levels after treatment with black cumin seed or oil. In studies of patients with hyperlipidemia, treatment with black cumin lowered total cholesterol, low-density lipoprotein cholesterol, and triglycerides. A well-designed, randomized, double-blind, placebo-controlled, two-arm, parallel study with a large number of patients with psoriasis5 showed a synergic effect of black cumin seed oil and garlic (Allium sativum, Amaryllidaceae) oil in improving dyslipidemia. The combination of the two herbs with simvastatin, a pharmaceutical statin drug, significantly improved lipid profiles more than simvastatin did alone. Although the identified studies reported positive effects of black cumin seed on glycemic control and lipid profile, the differences in the dose and type of plant extract, dietary intake, physical activity level, baseline biochemical profile, duration of study, type of disease, ethnicity of the patients, and genotype could have affected the results, suggest the review authors.

black-cumin-herb

In a study investigating the protective effect of black cumin against methotrexate-induced hepatotoxicity in 40 children newly diagnosed with acute lymphoblastic leukemia,6 a nonsignificant increase was observed in markers of liver damage in those consuming black cumin oil for one week after each methotrexate dose. The increase in those markers in patients treated with placebo was significant, resulting in a significant between-group difference. “These results demonstrated the antihepatotoxic effect of N. Sativa oil,” conclude the review authors.

The effects of black cumin on aging and memory and the effects of TQ on epilepsy were reported in several studies. Bin Sayeed et al. reported that black cumin supplementation could prevent or slow down the complications of Alzheimer’s disease.7 In a double-blind, crossover, clinical study,8 the investigators reported a reduction in the frequency of seizures after a four-week adjuvant therapy of TQ compared with baseline and with placebo.

Reports of cardiovascular effects of black cumin suggested to be due to TQ, polyphenols, flavonoids, and unsaturated fatty acids of the plant, are mixed. Dehkordi and Kamkhah9 showed that a two-month supplementation with black cumin seed extract in patients with mild hypertension led to significantly reduced levels of both systolic and diastolic blood pressure compared with baseline. In a long-term, randomized, double-blind trial of 73 adults,10 Qidwai et al. found favorable effects of powdered black cumin seed capsules on lipid and blood sugar levels, blood pressure, and body weight; however, the results were not statistically significant because of the small sample size.

The respiratory effects of black cumin reported in the studies include a preventive effect on asthma and a prophylactic effect on respiratory disorders. Boskabady et al.11 concluded that the use of black cumin extract led to improvement in all asthma symptoms in the study patients. A randomized, double-blind, placebo-controlled trial examining the prophylactic effect of a two-month daily intake of a black cumin seed aqueous extract in chemical war victims reported significant improvements in all respiratory symptoms, chest wheezing, and pulmonary function test values, with no adverse effects.12 “Taking into account the bronchodilatory as well as anti-inflammatory effects of TQ and its high content in the plant oil, it was found to be responsible for those effects,” the review authors write.

A two-month supplementation with a daily intake of 5 mL black cumin oil significantly improved the sperm count, motility, morphology, semen volume, pH, and round cells in infertile men compared with placebo, without any adverse effects.13 The review authors suggest that “the antioxidant activity of TQ, vitamin E, selenium, and unsaturated fatty acid contents of the N. Sativa oil may be responsible for this effect of the plant.”

Confounding factors and limitations of the studies reviewed here make data interpretation difficult, say the authors. Limitations include the failure to explain the design of placebo or control groups, to include baseline biochemical profiles, to identify the active constituent and the phytochemical assessment and formulation of the applied agents, to mention the type of randomization, and to control the patients’ diet. Some study results are limited by small sample sizes and short durations.

Although the findings of this review support the traditional use of black cumin, the authors state that “more precise clinical studies regarding the effect of N. Sativa and its constituents on various diseases are needed to ensure their exact clinical efficacy as well as the mechanisms of each effect.”

References

1Woo CC, Kumar AP, Sethi G, Tan KH. Thymoquinone: a potential cure for inflammatory disorders and cancer. Biochem Pharmacol. 2012;83(4):443-451.

2Gheita TA, Kenawy SA. Effectiveness of Nigella sativa oil in the management of rheumatoid arthritis patients: a placebo-controlled study. Phytother Res. 2012;26(8):1246-1248.

3Ghorbanibirgani A, Khalili A, Rokhafrooz D. Comparing Nigella sativa oil and fish oil in the treatment of vitiligo. Iran Red Crescent Med J. 2014;16(6):e4515. doi: 10.5812/ircmj.4515.

4Abdel-Moneim A, Morsy BM, Mahmoud AM, Abo-Seif MA, Zanaty MI. Beneficial therapeutic effects of Nigella sativa and/or Zingiber officinale in HCV patients in Egypt. EXCLI J. 2013;12:943-955.

5Ahmad Alobaidi AH. Effect of Nigella sativa and Allium sativum coadministered [sic] with simvastatin in dyslipidemia patients: a prospective, randomized, double-blind trial. Antiinflamm Antiallergy Agents Med Chem. 2014;13(1):68-74.

6Hagag AA, Elaal AMA, Elsheik A, Elzamarany EA. Protective effect of Nigella sativa oil against methotrexate-induced hepatotoxicity in children with acute lymphoblastic leukemia. J Leuk (Los Angel). 2013;1(4):123. doi: 10.4172/2329-6917.1000123.

7Bin Sayeed MS, Asaduzzaman M, Morshed H, Hossain MM, Kadir MF, Rahman MR. The effect of Nigella sativa Linn. seed on memory, attention, and cognition in healthy human volunteers. J Ethnopharmacol. 2013;148(3):780-786.

8Akhondian J, Kianifar H, Raoofziaee M, Moayedpour A, Toosi MB, Khajedaluee M. The effect of thymoquinone on intractable pediatric seizures (pilot study). Epilepsy Res. 2011;93(1):39-43.

9Dehkordi FR, Kamkhah AF. The antihypertensive effect of Nigella sativa seed extracts in patients with mild hypertension. Fundam Clin Pharmacol. 2008;22(4):447-452.

10Qidwai W, Hamza HB, Qureshi R, Gilani A. Effectiveness, safety, and tolerability of powdered Nigella sativa (kalonji) seed in capsules on serum lipid levels, blood sugar, blood pressure, and body weight in adults: results of a randomized, double-blind controlled trial. J Altern Complement Med. 2009;15(6):639-644.

11Boskabady MH, Javan H, Sajady M, Rakhshandeh H. The possible prophylactic effect of Nigella sativa seed extract in asthmatic patients. Fundam Clin Pharmacol. 2007;21(5):559-566.

12Boskabady MH, Farhadi J. The possible prophylactic effect of Nigella sativa seed aqueous extract on respiratory symptoms and pulmonary function tests on chemical war victims: a randomized, double-blind, placebo-controlled trial. J Altern Complement Med. 2008;14(9):1137-1144.

13Kolahdooz M, Nasri S, Modarres SZ, Kianbakht S, Huseini HF. Effects of Nigella sativa L. seed oil on abnormal semen quality in infertile men: a randomized, double-blind, placebo-controlled clinical trial. Phytomedicine. 2014;21(6):901-905.