Black Seeds: Potential Health Benefits : Nutrition Today

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Food Science

Black Seeds

Potential Health Benefits

Singletary, Keith W. PhD

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Nutrition Today 57(6):p 348-366, 11/12 2022. | DOI: 10.1097/NT.0000000000000580
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Abstract

Nigella sativa (family Ranunculaceae) (NS) is an annual flowering plant indigenous to southern Europe, northern Africa, and southwest Asia and is presently cultivated in numerous regions around the world. Its black, flat, triangular seeds are commonly referred to as black seeds because they usually turn black when exposed to air (Figure 1). Other names include black cumin and black caraway, although the seeds of NS are not related to these other spices. In addition, NS seeds are not to be confused with the seeds of Bunium persicum (family Apiaceae), also called black cumin and black caraway, which are slender, brown, and crescent shaped. In traditional Indian, Persian, Greek, and Arabic cultures, black seeds were variously referred to as kalonji, siyah daneh, melanthion, and habbat-al-barakah. These seeds have a flavor and aroma described as pungent, bitter, and metallic.1,2 The inclusion of this spice into culinary dishes varies widely depending on cultural preferences and individual palate because it is also known to provide an oniony, smoky accent. Along with fenugreek, cumin, fennel, and black mustard seeds, it is a component of the Bengali spice blend panch phoron. The Ethiopian spice mixture berbere contains black seed, cardamom, coriander, fenugreek, smoked paprika, and urfa chili. In India, it is a part of the spice blend used to make Punjabi gajar ka anchar, a carrot pickle, and for preparing a spicy mango pickle. It is frequently used in regional baked goods. Black seed can be sprinkled on Indian naan bread, Indian flatbread masala paratha, Turkish flat bread, the Algerian bread Khoubz b' Sanoudj, and the Armenian Easter bread choereg. In Palestinian cuisine, gizha is a dense black paste of roasted nigella seeds that traditionally is used in preparing breads and cakes such as the bittersweet gizha pie. Its other culinary uses are many. The oil can be drizzled on salads, added to dressings, and incorporated into curries, stews, and stir-fry dishes. Roasted seeds can garnish a variety of vegetable recipes. Moroccan chicken tangine may incorporate roasted black seeds (sanouj), both crushed and whole, to provide a hint of oregano-like flavor. The seeds may be added to coffee and tea. In Ethiopia, black seeds can flavor alcoholic beverages. In Greece and Cyprus, these seeds are uniquely added during pan-frying or grilling of a popular cheese called halloumi made from fresh sheep and goat milk.

F1
FIGURE 1.:
Nigella sativa.

Black seeds contain about 21% protein, 32% carbohydrates, and 38%–45% lipids. The content of bioactive phytochemicals in NS essential oil can vary depending on cultivation conditions, seed of origin, and methods of extraction.2–4 In general, the monoterpene diketone thymoquinone (2-isopropyl-5-methylbenzo-1,4-quinone) (TQ), present at levels of 30%–48%, and the monocyclic monoterpene p-cymene, present at levels of 7%–15%, are the 2 major components, although the phenolic monoterpene carvacrol (6%–12%) is another important phytochemical (Figure 2). Carvacrol is a main constituent in essential oils from plants of the genera Origanum and Thymus along with smaller amounts of TQ.

F2
FIGURE 2.:
Nigella sativa chemicals.

Black seeds have a long history of use in traditional medicine dating back to ancient Greeks, Romans and Egyptians, and were accorded potent healing power in Islamic texts.5–7 It is commonly cited in Arabic, Persian, and Ayurvedic medicines for treatment of such diverse ailments as gastrointestinal and respiratory distress, headaches, toothaches, treatment of intestinal worms, and for alleviating menstrual and postpartum complications, to name a few. The dosages, forms, and routes of application of black seed used to treat diverse maladies likely vary among the traditional medicine systems of the Middle East, Africa, and India, and also specific disease-specific amounts may not be clearly articulated. For example, depending on individual tolerance to black seed oil, 1 to 2 tsp/d of oil may be consumed to help with diabetes, high blood cholesterol, and high blood pressure (BP). In Ayurveda, diverse general medicinal uses often called for mixing seeds with honey before intake, eating black seeds plain, chewing seeds to soothe a toothache, or inhaling vapors from a mix of hot water and black seed oil to alleviate respiratory distress. For topical applications, varying amounts of black seed oil may simply be placed on an affected area or more intensively massaged into a tissue for specified time periods. In light of these diverse folk remedies, recent preclinical investigations and clinical trials have evaluated black seed extracts and individual phytochemicals for potential usefulness in treating cardiometabolic disorders, arthritis and pain management, and respiratory inflammation.5,6,8–10 This narrative review summarizes current progress in these and other clinical trials and provides suggestions for future research.

METHODS

To provide evidence for potential health benefits of foods, ingredients, and plant constituents, data are gathered from a variety of scientific methods such as cell culture experiments, animal studies, and human clinical trials. Human studies are particularly important in determining public health recommendations, especially randomized controlled trials (RCTs) testing well-characterized treatments and applying appropriate statistical analyses. With this in mind, a search of the PubMed and Science Direct databases was conducted through August 2022, using terms that included Nigella sativa, black seeds, kalongi, thymoquinone, and carvacrol. Full reports of English-language publications and English-language abstracts of foreign-language articles from peer-reviewed journals were the primary sources of information. Although the quality of identified studies varied considerably, all relevant, published investigations were included in this overview so that the totality and diversity of information can be described, and issues for future research can be identified. Additional information was gleaned from bibliographies within these sources. Studies of black seed as a component within multi-ingredient preparations were not included in this overview.

BIOAVAILABILITY

Laboratory Studies

In laboratory experiments, TQ was reported to have good water solubility but poor stability, suggesting that the observed rapid degradation in an aqueous environment potentially limits its bioavailability.11 In rats given oral suspensions of TQ (10–20 mg/kg body weight), maximum blood concentrations (Cmax) of 4.5 to 68.5 μg/mL were reached within 2–4 hours. Circulation elimination half-life (t1/2) values of 2.1 to 9.4 hours12–15 also resulted. In 1 study, maximum tissue concentrations of TQ in the liver, heart, spleen, brain, and lungs of rats occurred at 2–4 hours postdosing,13 and in another report, clearance of TQ was slightly but significantly less in female versus male rats.15

Human Studies

The typical intake of NS in foods and beverages in different regions is not known. Moreover, information about the bioavailability of NS constituents after human consumption is lacking. Clearly, additional information about the absorption, distribution, and disposition of bioactive NS constituents in humans is needed.

BIOLOGICAL ACTIONS OF NS IN HUMANS

To date, more than 60 clinical trials have evaluated NS seed and its oil and extracts for beneficial actions toward cardiometabolic disorders. Also, at least 70 human studies examined the ability of NS to alleviate neurological, skin, and female disorders; oral and respiratory problems; and viral and bacterial infections. It is worth noting that in many trials, the chronic dosing of NS, especially at levels up to 5 g/d, is likely much higher than culinary amounts typically consumed as a flavoring for breads, salads, and spice blends. Also, among clinical studies evaluating the same disorder, the conduct and outcomes are collectively very heterogeneous. The reasons for this are numerous. The baseline characteristics and clinical conditions of patients differed widely. For some of these disorders, NS was provided along with different oral medications as part of standard therapy. Confounding factors such as diet and physical activity of participants were not consistently assessed. Experimental designs and quality of methodologies varied. Not all published reports were randomized controlled studies (RCTs). Furthermore, for studies with placebo controls, the form of the placebo varied or was not reported. For example, placebo constituents could be paraffin, mineral oil, sunflower oil, calcium lactate, brown sugar, wheat germ, or starch depending on the form of NS intervention. Numbers of subjects were generally small and durations of interventions were as short as 2 weeks to as long as 1 year. Forms of NS provided usually were oil or powder from crushed seeds. However, the chemical composition of samples administered and details of extract preparation were not consistently described. For example, the temperature during thermal processing of the seed can impact the subsequent content of TQ in the oil. All of these differences make it difficult to interpret exactly what the effects are due to.

Cardiometabolic Risk Factors

There is considerable interest in verifying the effectiveness of traditional medicines for improving the health of those with diabetics, hypercholesterolemia, and other similar conditions.16,17 The effects of NS intake on diverse cardiometabolic risk factors associated with type 2 diabetes mellitus, cardiovascular disease/coronary artery disease, the metabolic syndrome (MetS), dyslipidemia, and hypertension are summarized in Table 1. Most studies reported a beneficial action of NS oil and seed powder on blood glucose and lipid levels. For the other risk factors measured in Table 1, such as BP and body mass index (BMI), outcomes of treatment seemed inconsistent.83 Several meta-analyses evaluated some of these trials to determine statistically significant relationships between NS treatment and specific health conditions.84–87 The choice of human trials to include in these analyses differed substantially among these reports. Data from as few as 7 clinical trials85 to as many as 50 clinical trials87 were chosen for examination. It is important to point out that the quality of trials chosen for each meta-analysis varied considerably. Using such methods as calculating the Jadad score or examining adherence to Cochrane guidelines, an assessment of methodological quality was determined by the authors of these meta-analyses. For example, among those 17 trials selected from Table 1 for the meta-analysis of Sahebkar et al,84 7 trials were considered of low quality,22,26,65–68,72 5 were of intermediate quality,27,36,37,41,65 and only 5 were of high quality.21,28,29,38,64 Among these many trials examined in the meta-analyses, the amounts of oil ingested varied from 100 mg/d to 5 g/d, and seed powder, from 0.5 to 5.0 g/d. Durations of treatments varied from 2 weeks to 1 year. Compared with placebo controls, treatments with NS were associated with significant decreases in total cholesterol (weighted mean difference [WMD], −15.65 to −22.99 mg/dL), low-density lipoprotein cholesterol (LDL; WMD, −14.10 to −22.38 mg/dL), fasting blood glucose (WMD, −9.93 to −17.84 mg/dL), and glycosylated hemoglobin (WMD, −0.45 to −0.71%). Responses of high-density lipoprotein cholesterol and triglycerides were inconsistent, and 1 analysis87 noted no effect of NS on serum insulin and insulin resistance. Subgroup analyses in 1 meta-analysis84 suggested that oral intake of oil was superior to that of seed powder in improving total cholesterol and LDL levels. From another analysis,86 NS had a greater effect on glycemic control in subjects diagnosed with type 2 diabetes mellitus and the MetS, compared with healthy individuals or those with other conditions. These differences in apparent efficacy of NS form and in healthy individuals versus those with MetS need further confirmation. Additional insights come from a meta-analysis of nonalcoholic fatty liver disease in Iran and Pakistan.88 Treatment with NS was associated with significant decreases in alanine aminotransferase, aspartate aminotransferase, LDL, and triglyceride levels and an increase in high-density lipoprotein. No effect on BMI was observed. Two meta-analyses examined the influence of NS on anthropometric indices.89,90 Compared with placebos, significant decreases in body weight (WMD, −1.76 to −2.11 kg) and BMI (WMD, −0.85 to −1.16 kg/m2) were found. A recent review91 recommended NS supplementation along with diet modification and increased physical activity as a potentially beneficial contributor to body weight reduction strategies. Blood pressure was examined in a meta-analysis of 11 trials,92 which found that NS intake, compared with placebos, significantly reduced systolic BP (WMD, −3.26 mm Hg) and diastolic BP (WMD, −2.80 mm Hg). This action of NS occurred in both normotensive and hypertensive individuals. Stratification of outcomes according to type of NS showed that significant improvements in systolic and diastolic BP were evident with NS powder but not with the oil, a result that also deserves additional study. Taken together, these studies underscore the lack of clarity regarding the comparative benefit of oil versus powder for specific metabolic abnormalities, the magnitude of the effects of the doses that produce consistent improvements, and the length of treatments to obtain maximum efficacy. Also, the potential of NS as an adjunctive treatment in diabetes deserves further validation and clarification because 1 analysis85 suggested that the ability of NS to improve glycosylated hemoglobin concentrations was equivalent to that following the use of dipeptidyl peptidase-4 inhibitors. Regarding safety, the numerous human trials and meta-analyses confirm that any side effects from the doses and durations of NS intake examined, such as nausea, anorexia, and dyspepsia, were mild and transient.83–86

TABLE 1 - Effects of Nigella Sativa on Cardiometabolic Risk Factors
Condition Sample Dose/Duration
(Sample Size)
Outcomes Reference
Main Others
Normal individuals Seed powder 2 g/d (n = 9), control (n = 7); 1 wk #↓FBG, ↓TC NE: TG ↑Creatinine NE: BUN, uric acid 18
2 g/d (n = 10); 1 wk #↓FBG, ↓TC, ↑HDL, ↓clotting time Creatinine NE: CK, PRL 19
1 g/d (n = 15), control (n = 15); 4 wk, ♂ only ▲NE: FBG, SI, insulin sensitivity, TC, HDL, LDL, TG 20
1 g/d (n = 20), control (n = 20); 9 wk #NE: TC, TG, LDL, HDL, SBP, DBP NE: creatinine, AST, ALT 21
1.6 g/d (n = 55), control (n = 55), crossover; 12 wk, ♀ only ▲NE: FBG, TC, TG, LDL, HDL, BMI 22
Hot tea from 5 g seeds/d; 6 mo #↓FBG, ↓PPBG, ↓HbA1C, ↓TC, ↓TG, ↓LDL, ↑HDL ↑PON-1, ↓BUN, ↓serum total biliribin 23,24
Oil Oil from 2 g seeds (n = 35), control (n = 35); 8 wk #↓FBG, ↓TC, ↑HDL ↓Creatinine, ↓clotting time
NE: CK, PRL
19
5 mL/d (n = 35), control (n = 35); 8 wk #↓SBP, ↓DBP NE: BMI NE: Creatinine, BUN, AST, ALT, ALP 25
Obese/overweight Seed powder 3 g/d (n = 19), control (n = 20); 3 mo, ♂ only ▲↓BW, ↓WC, complaints of obesity
NE: SBP, DBP, FBG, TG, HDL
NE: T, uric acid, creatinine, AST, ALT, adiponectin 26
2 g/d (n = 8), control (n = 8) plus aerobic training; 8 wk, ♀ only ▲↓LDL, ↑HDL NE: TC, TG, BMI 27
Oil 3 g/d (n = 25-43), control (n = 24-41) plus low-calorie diet; 8 wk, ♀ only ▲↓TG, ↓LDL, ↓BW
NE: BMI, SBP, DBP, TC, LDL
↓TNF-α, ↓CRP, ↑RBC SOD
NE: IL-6, RBC GPx, TAC, MDA
28–30
2 g/d (n = 19), control (n = 22) plus low-calorie diet; 8 wk, ♀ only ▲↓LDL, ↑HDL, ↓SBP, ↓BMI, ↓WC, ↓%BF
NE: WHR, TC, TG, DBP
↓TNF-α, ↑PPAR-γ, ↓AST, ↓MDA, ↓TAC, ↑adiponectin
NE: ALT, ALP, BMR, fat free mass
31–33
Prediabetes Oil 900 mg/d (n = 35); 6 mo #↓BMI, ↓FBG, ↓HbA1C, ↓SI, ↓HOMA-IR, ↓TC, ↓TG, ↓LDL, ↑HDL
NE: PPBG,
HOMA-β
↓TNF-α, ↑SIRT1 NE: p53 34
T2DM Oil 5 mL/d + standard treatment (n = 30), control standard treatment (n = 30); 6 wk ▲↓FBG, ↓LDL, ↓TC
NE: PPBG, HDL, TG
35
5 mL/d (n = 35), control (n = 35); 3 mo ▲↓FBG, ↓PPBG, ↓HbA1C, ↓BMI
NE: TC, TG, LDL, HDL
NE: creatinine, ALT, AST, ALP 36
1 g/d (n = 23), control (n = 20); 8 wk ▲↓TG, ↓TC, ↓LDL NE: HDL 37
3 g/d (n = 34), control (n = 33), 12 wk ▲↓FBG, ↓HbA1C, ↓TG, ↓LDL
NE: TC, BMI, HDL, SI, HOMA-IR
38
500 mg/d (n = 23), control (n = 20); 8 wk ▲↓TG, ↓LDL, ↓TC NE: HDL 37
q.35 g/d (n = 21), 2 g/d metformin (n = 23); 12 wk #↓FBG, ↓BMI, ↓WC (oil comparable to metformin in ↓FBG+ BMI + WC)
NE: PPBG, SI, HbA1C, IR, %B, TC, TG, LDL, HDL
NE: creatinine, AST, ALT, TAC 39
1 g/d (n = 27), control (n = 23); 8 wk ▲↓FBG, ↓TG, ↓TC, ↓LDL, ↑HDL ↓CRP, ↓MDA 40
1 g/d (n = 23), control (n = 20); 8 wk ▲↓FBG, ↓HbA1C, ↓TG, ↓TC, ↓LDL, ↓SBP, ↓DBP, ↓BMI, ↑SI NE: HOMA-IR, HDL 41
Oil from 0.7 g seeds/d (n = 40), control (n = 40); 40 d #↓FBG, ↑SI, ↑AST NE: ALT, BUN, platelet/leukocyte count 42
T2DM + hemodialysis Oil 2 g/d (n = 20), control (n = 21); 12 wk ▲↓FBG, ↓HbA1C NE: SI ↑SOD, ↑TAC, ↓MDA, ↓CRP 43
T2DM + CKD Oil 2.5 mL/d (n = 32), control (n = 31); 12 wk ▲↑%Hb
NE: FBG, PPBG, Na+, Ca++
↓Creatinine, ↑GFR, ↓K+, ↓urinary protein 44
T2DM Seed powder 1 g/d (n = 23), 2 g/d (n = 26), 3 g/d (n = 19); 12 wk # 1 g/d: NE: all measures
#2 g/d: ↓FBG, ↓IR, ↓HbA1C, ↓TG, ↓TC, ↓LDL, ↑HOMA-β NE: BMI, HDL #3 g/d: ↓FBG, ↓HbA1C, ↓TC NE: IR, HOMA-β, BMI, TG, LDL, HDL
NE: C-peptide 45,46
2 g/d (n = 26), control (n = 26); 12 mo ▲↓LV dimension at systole, ↑%EF, ↑%FS
NE: diastolic functions
47
2 g/d (n = 48), control (n = 48); 1 y ▲↓FBG, ↓HbA1C
NE: HOMA-IR, ß-cell function
↑TAC, ↑GSH, ↓TBARS
NE: C-peptide, SOD, CAT
48
2 g/d (n = 39), control (n = 39); 1 y ▲↓TC, ↓LDL, ↓DBP, ↓HR, ↓MAP
NE: FBG, TG, HDL, SBP, BMI
NE: renal + liver function 49
Methanol extract 2 g/d (n = 10); 8 wk #↓FBG, ↓SI, ↓TC, ↓TG, ↑HDL, ↓HOMA-IR, ↑HOMA-β
NE: BMI, %BF, LBM
↓CRP, ↓AST, ↓ALT, ↓ALP 50
Tea Hot tea from 5 g seeds/d (n = 41); 6 mo #↓FBG, ↓PPBG, ↓HbA1C, ↓TC, ↓TG, ↓LDL, ↑HDL ↓BUN, ↑PON-1, ↓serum total bilirubin 23,24
MetS Oil 5 mL/d (n = 30), control (n = 30), all + standard therapy; 6 wk ▲NE: BMI, WC 51
1.5 mL/d (n = 33), 3 mL/d (n = 33), control (n = 33), all + standard therapy; 20 d ▲↓HbA1C
NE: FBG, SBP, DBP, BMI
52
Seed powder 1 g/d (n = 40), control (n = 40); 8 wk ▲↓FBG, ↓LDL, ↓HbA1C
NE: PPBG, TG, HDL
53
1 g/d (n = 18), control (n = 17); 2 mo, ♀ only ▲↓LDL, ↓TC, ↓TG, ↑HDL
NE: FBG, BW
54
1.5 g/d (n = 62), control (n = 63); 8 wk ▲↓FBG, ↓TC, ↓TG, ↓LDL, ↑HDL
NE: BMI, SBP, DBP, %BF
NE: CRP 55
500 mg/d (n = 81), control (n = 78); 6 wk ▲↓FBG, ↓LDL, ↓HDL
NE: PPBG, TC, TG, BMI, SBP, DBP
56
3 g/d in bread (n = 27), control bread (n = 24); 2 mo ▲NE: FBG, BMI, WC, DBP, SBP, TC, TG, LDL, HDL, Apo-A, Apo-B NE: CRP 57,58
500 mg/d (n = 70), control (n = 70); 8 wk ♀ only ▲↓FBG, ↓TC, ↓TG, ↓LDL
NE: HbA1C, BMI, HDL
↓sICAM, ↓sVCAM, ↑TAC, ↓MDA
NE: AIP
59
CAD Oil 2 g/d (n = 25), control (n = 24); 8 wk ▲FBG, SBP, DBP, BMI, WC NE: TC, TG, LDL, HDL, SI, HOMA-IR, QUICKI 60,61
1 g/d (n = 23), control (n = 24); 2 mo ▲↑brachial FMD, ↑plasma nitrate NE: VCAM-1, ICAM-1 62
Seed powder 500 mg/d (n = 40), control (n = 40); 6 mo ▲NE: TC, TG, LDL, HDL 63
Dyslipidemia Seed powder 2 g/d (n = 39), control (n = 34); 6 wk ▲NE: FBG, TC, LDL, HDL, BMI NE: creatinine 64
2 g crushed seed/d (n = 37), control (n = 37); 4 wk #↓TC, ↓TG, ↓LDL NE: FBG, HDL 65
2 tsp/d (n = 27-30), control (n = 30); 4-6 wk
2 g/d niacin (n = 28); 6 wk
#↓LDL, ↑HDL, ↓BW
(comparable with niacin)
66,67
1 g/d (n = 19), control (n = 18); 2 mo, ♀ only ▲↓FBG, ↓TC, ↓TG, ↓LDL
NE: HDL, SBP, DBP
68
2 g/d (n = 20); 30 d, ♂ only #↓TC, ↓TG, ↓LDL, ↑HDL 69
Hypertension Oil 1 mL/d (n = 80), control (n = 80); 45 d #↓FBG, ↓TC, ↓LDL, ↑HDL, ↓BMI, ↓BP
NE: TG
70
5 mL/d (n = 26), control (n = 29); 8 wk ▲↓FBG, ↓TC, ↓LDL, ↓SBP, ↓DBP
NE: TG, HDL
↓MDA 71
200 mg/d (n = 36), 400 mg/d (n = 39), control (n = 33); 8 wk #↓TC, ↓LDL, ↓SBP, ↓DBP
NE: TG, HDL, BMI
NE: BUN, AST, ALT, ALP 72
600 mg/d (n = 38), control (n = 38); 28 d ▲NE: SBP, DBP 73
NAFLD Oil 5 mL/d (n = 60), control (n = 60); 3 mo ▲↓LDL, ↓TG, ↑HDL, ↓steatosis NE: BMI ↓AST, ↓ALT
NE: BUN creatinine
74
1 g/d (n = 22), control (n = 22); 8 wk #↓FBG, ↓TC, ↓LDL, ↑HDL
NE: SI, BMI, DBP, SBP, GGT
↓AST, ↓ALT, ↓CRP, ↓IL-6, ↓TNF-α NE: GGT, adiponectin, leptin 75,76
Seed powder 2 g/d (n = 35), control (n = 35); 12 wk #↓BMI, ↓fatty liver ↓AST, ↓ALT, ↓GGT 77
2 g/d (n = 22), control (n = 21); 12 wk ▲↓FBG, ↓SI, ↓HOMA-IR, ↑QUICKI, ↓steatosis NE: TC, TG, LDL, HDL, BMI ↓TNF-α
NE: NF-kB, CRP, ALT, AST, GGT
78,79
Hashimoto's thyroiditis Seed powder 2 g/d (n = 20), control (n = 20); 8 wk #↑SI, ↑HDL, ↓LDL, ↓TG, ↑HOMA-IR, ↓BMI, ↓AIP
NE: FBG, TC
↓Anti-TPO, ↓TSH, ↑T3, ↓IL-23, ↓VEGF NE: T4, nefstatin-1, TGF-ß 80–82
Abbreviations: AIP, atherogenic index of plasma; ALP, alkaline phosphatase; ALT, alanine aminotransferase; Apo-A, apolipoprotein-A; Apo-B, apolipoprotein-B; AST, aspartate aminotransferase; %B, secretory function of pancreatic ß cells; BF, body fat; BMI, body mass index; BMR, basal metabolic rate; BP, blood pressure; BUN, blood urea nitrogen; BW, body weight; CAD, coronary artery disease; CAT, catalase; CK, creatine kinase; CKD, chronic kidney disease; CRP, C-reactive protein; DBP, diastolic blood pressure; EF, ejection fraction; FBG, fasting blood glucose; FMD, flow-mediated dilation; FS, fractional shortening; GFR, glomerular filtration rate; GGT, γ-glutamyl transpeptidase; GPx, glutathione peroxidase; GSH, glutathione; Hb, hemoglobin; HbA1C, glycosylated hemoglobin; HDL, high-density lipoprotein cholesterol; HOMA-IR, homeostatic model assessment for insulin resistance; HOMA-β, homeostatic model assessment of β-cell function; HR, heart rate; ICAM-1, intracellular adhesion molecule-1; IL, interleukin; IR, insulin resistance; LBM, lean body mass; LDL, low-density lipoprotein cholesterol; LV, left ventricular; MAP, mean arterial pressure; MDA, serum malondialdehyde; MetS, metabolic syndrome; NAFLD, nonalcoholic fatty liver disease; NE, no statistically significant effect; NF-kB, nuclear factor kappa B; PON-1, serum paraoxonase-1; PPAR-γ, peroxisome proliferator-activated receptor-γ; PPBG, postprandial blood glucose; PRL, prolactin; QUICKI, quantitative insulin sensitivity check index; RBC, red blood cell; SBP, systolic blood pressure; SI, serum insulin; sICAM, soluble intercellular adhesion molecule; SIRT1, sirtuin-1; SOD, superoxide dismutase; sVCAM, soluble vascular cellular adhesion molecule; T, testosterone; T3, triiodothyronine; T4, thyroxine; TAC, serum total antioxidant capacity; TBARS, thiobarbituric acid reactive substances; TC, total cholesterol; TG, serum triglycerides; TGF-ß, transforming growth factor-ß; TNF-α, tumor necrosis factor-α; TSH, thyroid stimulating hormone; T2DM, type 2 diabetes mellitus; TPO, thyroid peroxidase; VCAM-1, vascular cellular adhesion molecule-1; VEGF-1, vascular endothelial growth factor-1; WC, waist circumference; WHR, waist-to-height ratio.
#, statistical comparison between after treatment and baseline; ▲, statistical comparison between treatment and placebo control.

Potential mechanisms by which NS may be promoting these cardiometabolic actions were not consistently addressed in clinical trials. Modifications by NS of mediators and signaling pathways associated with antioxidative and anti-inflammatory systems were inconsistent.87 Extensive, recent reviews of preclinical experiments examining NS and TQ mechanisms of action have been published.8,9,87,91–95

Table 2 summarizes human studies evaluating NS treatment for neurological conditions. Oral intake of oil was most frequently evaluated and administered at levels from 200 mg/d to 1 g/d. Culinary use of this NS oil seems to be similar to this range of doses. Nine trials assessed effects on arthritic disorders. In most of the studies, NS administration, either orally or topically, alleviated disease symptoms. The only arthritis trial showing no effects of NS on pain scores evaluated seed powder109 processed with vinegar as directed in Iranian traditional medicine protocols.112 This vinegar processing eliminates TQ,113 suggesting that deletion of TQ may partly explain the lack of efficacy in this RCT. This study also highlights the importance of providing adequate details about preparing or processing NS samples for human intake so that the causes of variability among trials can be better assessed. Recent reviews112,114–117 suggest that NS may have potential to alleviate symptoms of neurodegenerative diseases, but a number of additional high-quality clinical trials with larger study populations are clearly needed. Moreover, to date, no consistent evidence for possible mechanisms of action of NS has been determined from these human investigations.

TABLE 2 - Effects of Nigella Sativa on Neurological Conditions in Humans
Condition Sample Dose/Duration
(Sample Size)
Outcomes Reference
Main Other
Normal individuals Seed powder 1 g/d (n = 20, control (n = 20; 9 wk #↑Memory, ↑attention, ↑cognition 21
500 mg/d (n = 24), control (n = 24); 4 wk, adolescent ♂ ▲ NE: mood, alertness, anxiety, recall 96
Oil 200 mg/d (n = 15); 28 d #↑NREM, ↑REM, ↑total sleep time, ↓sleep latency, ↓sleep disturbance, ↓anxiety, ↓stress ↓Serum cortisol
NE: hematologic values, depression, AST, ALT, creatinine
97
Depression Oil 1 g/d (n = 26), control (n = 26), all + sertraline; 10 wk ▲↓Depression, ↓anxiety, ↓stress ↑BDNF 98
Intractable pediatric seizures Seed H2O-extract 40 mg/kg TID (n = 20), control (n = 20); all + antiepilepsy drug; 4 wk ▲↓Seizure frequency, ↑parental QOL 99
Oil 40-80 mg/kg/d (n = 22), control (n = 22), all + antiepilepsy drug; 4 wk ▲NE: seizure frequency or severity NE: TAC, MDA 100
Thymoquinone 1 mg/kg/d (n = 22), control (n = 22), all + antiepilepsy drug; 4 wk ▲↓Seizure frequency, ↑parental QOL NE: ALT, AST, ALP, BUN, creatinine 101
Rheumatoid arthritis Oil 1 g/d (n = 40), control (n = 40); 1 mo #↓Morning stiffness, ↓swollen joints, ↓pain, ↓disease activity score 102
1 g/d (n = 23), control (n = 16); 8 wk, ♀ only ▲↓Disease activity score
NE: BMI, swollen joints
↓%CD8+ cells, ↑%CD4 + CD25+ Treg cells
NE: TAC, SOD, CAT, MDA, TNF-α, IL-10, NO
103,104
2 g/d + vitamin E (n = 28); 2 mo #↓ESR
NE: rheumatoid factor
↓creatinine, ↓erythrocyte SOD
NE: ALT, AST, CRP
105
Osteoarthritis Seed powder 2 g/d (n = 37), control (n = 40); 12 wk ▲NE: pain scores 106
Oil 1 mL on knee/TID (n = 40), 325 mg acetaminophen/TID (n = 40); 3 wk #↓Pain, oil superior to acetaminophen 107
Rub oil on knee 30 min, 3×/wk (n = 30), control (n = 30); 1 mo #↓Pain 108
1 mL on knee 2×/d (n = 25), 1 mL 1% diclofenac on knee 2×/d (n = 25); 21 d ▲↓Pain, oil superior to diclofenac 109
2.5 mL oral seed oil 2×/d + topical mineral oil 3×/d (n = 13), 2.5 mL oral mineral oil 2×/d + topical seed oil 3×/d (n = 14), control: 2.5 mL oral mineral oil 2×/d + topical mineral oil (n = 13) 3×/d; 6 wk ▲Oral oil:
NE: pain, stiffness, physical function
▲Topical oil:
↓pain, ↑physical function
NE: stiffness
110
Psoriatic arthritis Oil Case report: oil on skin daily, 1 wk.
10 g oil/d, 90 d
#↓Skin plaques, ↓arthralgias, ↓disease activity index.
(Oil superior to prior treatments with celecoxib, etanercept, indomethacin+ methotrexate.)
111
Abbreviations: ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; BDNF, brain-derived neurotrophic factor; BMI, body mass index; BUN, blood urea nitrogen; CAT, catalase; IL-10, interleukin-10; CRP, C-reactive protein; MDA, malondialdehyde; NE, no statistically significant effect; NO, nitric oxide; NREM, non–rapid eye movement; QOL, quality of life; REM, rapid eye movement; SOD, superoxide dismutase; TAC, total antioxidant capacity; TID, 3 times a day, every 8 hours; TNF-α, tumor necrosis factor-α.
#, statistical comparison of treatment outcome versus baseline condition; ▲, statistical comparison of treatment outcome versus placebo control outcome.

Table 3 summarizes more than 20 human trials evaluating NS for treatment of respiratory disorders. Subjects in these trials were ill; they exhibited different baseline symptoms associated with allergic conditions, chronic obstructive pulmonary disease, and pulmonary consequences of exposure to chemical warfare agents. Furthermore, multiple forms of NS were administered, including seed powder, oil, hot water extracts, and individual NS constituents. These interventions were administered by multiple routes, including by oral intake of seed powder, crushed seed, oil, or hot water extracts; by inhalation of volatile odors from oil and crushed seeds; or by nasal sprays or drops. Dosing was either alone or as a supplement to other therapies. The quality and design of trials differed considerably in the number of subjects recruited (5–115 participants), durations of treatment (4 days-3 months), and adherence to standard RCT methodology. Despite this variation, most investigations reported improvements in subjective clinical symptoms of respiratory distress, although, because blinding and disguising of placebo controls were inconsistent, it is difficult to know if the effect was truly due to NS. Some trials reported the effect of NS on pulmonary function test (PFT) scores, which are quantitative evaluations of lung function based on scores from different measures of health, such as lung volume, capacity, and rates of flow. Not all trials used the same individual pulmonary tests to determine PFT scores. Although overall PFT scores may have improved after NS treatment among the trials, there was considerable variation in the magnitude of responses to NS among individual lung function tests selected and between healthy subjects and those with respiratory distress. One meta-analysis143,144 evaluated NS for control of asthma using data from 4 RCTs. Supplementation with NS was associated with significant increases in asthma control test (ACT) scores and, for values of the lung test, forced expiratory volume at 1 second but had no significant effect on another lung test, peak expiratory flow rate, nor on interleukin-4 and interferon-gamma levels. This suggests that in addition to the need to duplicate this work, additional characterization of the specific responses to NS dosing for these different lung function tests is needed, especially because they may provide insights into potential NS mechanisms of action. No consistent effects of NS on anti-inflammatory and antioxidant biomarkers were evident in these studies. Of note, administration of the single agent carvacrol, a monoterpene phenolic present in NS essential oil, showed improved outcomes at least for some respiratory issues. This suggests that other phytochemicals in NS in addition to TQ are likely working collectively to improve these measures. In light of these improvements in respiratory symptoms after NS treatment, additional research to reproduce these findings and to characterize the forms of NS that are most effective for managing specific respiratory conditions is needed. This includes determining the doses and durations of treatment that consistently produce measurable improvements in subjective symptoms and identifying biomarkers of systemic inflammation and oxidative stress affected by NS in clinical trials. Whether NS can be useful as an adjunct to standard therapies needs to be clarified, especially if they are used in culinary doses rather than medicines. Potential mechanisms of action of NS affecting respiratory, allergic, and immunological disorders observed in clinical and experimental investigations have been reviewed elsewhere.145,146

TABLE 3 - Effect of Nigella Sativa on Human Respiratory Disorders
Condition Sample Dose/Duration
(Sample Size)
Outcomes Reference
Main Others
Allergic and immunologic disorders, asthma Seed powder 2 g/d + immunotherapy (n = 12), control immunotherapy (n = 12); 30 d ▲↑PMN % phagocytosis+% intracell killing activity 118
2 g/d + inhalation therapy (n = 26), control inhalation therapy (n = 26); 3 mo #↑FEF 25%-57%, ↓variability of FEV1 + PEFR, ↑ACT scores ↓IgE+ FeNO, ↑IFN-γ
NE: IL-4, IL-10, IL-17A
119
2 g crushed seed +1 tsp honey/d, also inhale crushed seed odor 3×/d (n = 5); 3 mo #↑FVC
NE: FEV1, PEFR
↓BUN
NE: ALP, AST, ALT, creatinine
120
15 mg/kg bw/d + immunotherapy (n = 8), control+ immunotherapy (n = 7); 14 wk #↑ACT scores NE: Th17 cells, CD4+CD25+Foxp3+Treg cells, CD4+IL-10+ cells 121,122
Oil 1.5 g/d (n = 41), control (n = 22); 8 wk
3 g/d (n = 49); 6-8 wk
▲↓Clinical symptoms
#↓clinical symptoms
NE: IgE, eosinophils
NE: TC, LDL, HDL, ACTH, urine cortisol, lymphocyte subpopulation
123
0.1 mL/kg bw/d + standard therapy (n = 43), control standard therapy (n = 41); 14 d, children ▲↓Pulmonary index
NE: PEFR
124
~2.1 g/d (n = 115), control (n = 95); 6 wk ▲↓Clinical symptoms, ↑tolerability to aggravating factors
NE: asthma
↓IgE, ↓conjunctivitis
NE: urticaria
125
0.5 mL/d (n = 30), control (n = 28); 30 d ▲↓Nasal congestion, ↓turbinate hypertrophy, ↓mucosa pallor ↓Nasal IgE, ↑nasal eosinophils
NE: serum IgE+ eosinophils
126
1 g/d (n = 30), controls (n = 30); 4 wk ▲↑ACT scores, ↑daily functioning
NE: PFT (FEV1) score
↓Blood eosinophils NE: IgE 127
2 Nasal sprays (1 g)/d + standard therapy (n = 31), control 2 sprays/d 0.65% NaCl (n = 34); 8 wk ▲↓Clinical symptoms, ↓SNOT-22 scores, ↓sinus opacification 128
Daily nasal drops (seed powder in sesame seed oil) (n = 25), control sesame oil drops (n = 25); 28 d ▲↓Clinical symptoms, ↓SNOT-22 scores, ↓sinus inflammation + discharge + pain + congestion 129
Hot-H2O extract 15 mL 0.1 g%/kg bw/d (n = 15), control glucose solution (n = 14); 3 mo ▲↓Allergy + asthma symptoms, ↑pulmonary function (↑FEV1, ↑PEFR, ↑MEF), ↓inhaler use 130
50 mg/kg bw/d (n = 15),
100 mg/kg bw/d (n = 15),
6 mg/kg bw/d theophylline (n = 15); 4 d
#both doses: ↑PFT scores (↑FEV1, ↑PEFR, ↑MEF, ↑MMEF)
NS inferior to theophylline + salbutamol inhaler
131
100 mg/kg bw/d by inhalation (n = 18),
0.15 mg/kg bw/d prednisone; 3 wk
#↑FEV1, ↑FVC
NS inferior to prednisone
↑Serum Se+++ Ca+++ K++ Mg++ 132
Nigellone 0.56 mg/d (n = 60), control (n = 10); 4 mo #↓Asthma attacks, ↓use of rescue drugs 133
Carvacrol 1.2 mg/kg bw/d (n = 17), control (n = 16); 2 mo ▲↑MMEF, ↑FVC, ↑PEFR scores, ↓ respiratory symptoms ↑Serum thiols, ↑SOD, ↓nitrite, ↑IFN-γ, ↓IL-4, ↓CRP, ↓total + differential WBC
NE: MDA, CAT, IL-10, RBC, MCV
134,135
Chemical warfare victims Hot H2O extract 0.375 mL of 50 mg/mL/kg bw/d (n = 20), control (n = 20); 2 mo ▲↓Respiratory symptoms, ↑FVC, ↑FEV1, ↑MEF, ↑MMEF scores, ↓inhaler use, ↓oral use ß-agonists + corticosteroid 136
Carvacrol 1.2 mg/kg bw/d (n = 10), placebo (n = 10); 2 mo ▲↑FEV1, ↑PEFR scores, ↓night wheeze, ↓night cough, ↓exercise-induced wheeze, ↓chest wheeze ↓IL-2, ↓IL-4, ↓IL-6, IL-8, ↑IL-10, ↑IFN-γ, ↓TNF-α, ↓EGF, ↓VEGF, ↓total + differential + WBC count, ↓MDA, ↑SOD, ↑thiols, ↑CAT
NE: MCP-1
137–139
COPD patients Oil 2 g/d + standard therapy (n = 47), control standard therapy (n = 44); 12 wk ▲↑FEV1, ↑FVC, ↑PEFR, ↑FEF scores ↓TBARS, ↓TNF-α, ↓IL-6, ↓protein carbonyls, ↑GPx, ↑SOD, ↑GSH
NE: MDA
140
Nasal discomfort of aging Oil 3 sprays/nostril 3×/d (n = 42), control 0.9% NaCl spray 3×/d (n = 42); 2 wk ▲↓Dryness+ nasal obstruction+ crusting
NE: mucociliary clearance, burning + itching sensations
141
Healthy adults Seed powder 2 g/d (n = 8); 30 d #↑PMN %phagocytosis+ %intracellular killing activity 118
2 g crushed seed + 1 tsp honey/d, inhale crushed seed odor 3×/d (n = 22); 3 mo #↑PEFR
NE: FVC, FEV1
↓Creatinine
NE: BUN, ALP, AST, ALT
120
Carvacrol 1 mg/kg bw/d (n = 15), 2 mg/kg bw/d (n = 15); 1 mo #1 mg: NE: FEV1, PEFR, MMEF, MEF scores #2 mg: ↑FEV1 NE: PEFR, MMEF, MEF NE: total + differential WBC count
NE: total + differential WBC count
142
Abbreviations: ACT, asthma control test; ACTH, adrenocorticotropic hormone; ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; BUN, blood urea nitrogen; bw, body weight; CAT, catalase; CRP, C-reactive protein; COPD, chronic obstructive pulmonary disease; EGF, epidermal growth factor; FEF, forced expiratory flow 25%–75%; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume at 1 second; FVC, forced volume capacity; GPx, glutathione peroxidase; GSH, glutathione; HDL, high-density lipoprotein cholesterol; IFN-γ, interferon-gamma; IgE, immunoglobulin E; IL, interleukin; LDL, low-density lipoprotein cholesterol; MCV, mean corpuscular volume; MCP-1, monocyte chemoattractant protein-1; MDA, malondialdehyde; MEF, maximal expiratory flow; MMEF, maximum mid-expiratory flow; NE, no statistically significant effect; PEFR, peak expiratory flow rate; PFT, pulmonary function test; PMN, polymorphonuclear neutrophils; RBC, red blood cell; SNOT, sinonasal outcome test; SOD, superoxide dismutase; TBARS, thiobarbituric acid reactive substances; TC, total cholesterol; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor; WBC, white blood cell.
▲, statistical comparison of treatment outcome versus placebo control outcome; #, statistical comparison of treatment outcome versus baseline condition.

Preliminary findings also suggest that NS powder, oil, and extracts have potential to relieve other disorders and conditions. However, much additional work must be done to confirm these effects. These trials examined suppression of Helicobacter pylori infections and dyspepsia,147–151 parasitic, bacterial and human immunodeficiency virus infections,152–157 hepatitis C symptoms,158,159 and Candida albicans–induced vaginitis.160 Other initial findings suggest that NS oil161 and TQ162 have potential to relieve SARS-2-COVID symptoms.163,164 In addition, NS was evaluated for treating skin disorders,165–170 for alleviating diverse oral health problems,171–178 and for relieving menstrual- and menopausal-related symptoms.22,179–182 In all these conditions, more investigations need to be done before the results can be regarded as secure.

SAFETY

The US Food and Drug Administration has approved NS seed as generally recognized as safe for use as a flavoring agent or adjuvant in food (21 CFR§182.20). Likewise, the Flavor and Extract Manufacturers of America considered black cumin and black caraway to be generally recognized as safe. In contrast, the essential oil is viewed as a chemical of concern by the European Food Safety Authority owing to the presence, although in trace amounts, of isoquinoline alkaloids such as nigellimine.183 As mentioned previously, the adverse effects of NS reported in human studies, such as nausea, anorexia, and dyspepsia, seem to be mild. Case reports of acute contact dermatitis184–190 and systematic reactions191–194 to NS have been documented. As a principal constituent of NS seed, TQ was evaluated in various toxicological studies.3,9,183,195,196 However, it should be noted that, at present, there are no sound estimates of important bioactive phytochemicals, such as nigellimine and TQ, in traditional NS products. Better characterization of a dose-response of these effects of NS would be helpful to determine whether side effects are more prevalent and troublesome for specific disease conditions. Contributing to this lack of information is that many research reports do not clearly describe whether a volatile or fixed oil of NS was provided to subjects, the contents of which can differ.197 Considering the collective data available, Hannan et al9 concluded that TQ and NS are suitable for long-term traditional use as food and medicine. However, Mashayekhi-Sardoo et al196 cautioned, based on human and preclinical studies, that TQ be considered as an “almost safe chemical” in light of the need for a more in-depth toxicological profile of TQ before its use as a therapeutic agent in humans. A phase I RCT in humans evaluated the safety of oral intake of an NS oil containing 5% TQ (total dose of 200 mg/d) for 90 days.198 This level of TQ is almost 10-fold higher than amounts in normal cold-pressed oil. No adverse effects on BP, BMI, hematological parameters, and markers of liver and kidney damage were observed. Similar outcomes were reported in another human study in which NS oil (2.72% TQ) was administered to 3 groups of subjects at doses of 1.5, 3.0, and 4.5 mL/d for 21 days.199 More recently, it was estimated that a safe daily dose of TQ is ≤48.6 mg/d for those adults desiring to consume commercial NS products.200

It should be noted also that caution may be warranted when considering oral use of NS as a galactogogue, as sometimes practiced in India and Iran. No scientifically valid clinical trials support this use in humans.201,202

An important aspect in assessing the safety of TQ and NS extracts is the wide variability in NS doses administered in clinical trials. Furthermore, the chemical composition of these NS samples is not routinely reported, which is important information because there can be wide differences in chemical content of samples, due in part to variety of plant harvested, environmental conditions, cultivation practices, and methods of extract isolation.3 These differences in dosing, along with the substantial variability in TQ content among these NS extracts, compound the uncertainly about the actual levels of human exposure to key constituents of NS.183 To further complicate this issue, it was recently reported that roasting of black seed dramatically decreases TQ content.203 Until there is greater adherence among investigators to an accepted standard of reporting chemical composition of samples, likely using TQ content as a starting point, this issue cannot be adequately resolved. This level of human exposure to NS bioactives also is critical for accurately evaluating how NS intake may affect drug metabolizing enzymes and transporters. There is evidence from human liver microsomes and a small clinical trial that TQ inhibits cytochrome P450 (CYP) enzymes,204–206 specifically CYP1A2, CYP2C9, CYP2D6, and CYP3A4. This may be problematic for some prescribed drugs, such as the immunosuppressive drugs cyclosporin and tacrolimus, the anticonvulsant carbamazepine, and some tricyclic antidepressants, particularly those with narrow therapeutic windows. Specifically, it was determined that there is a high probability that TQ can modify the metabolism of therapeutic agents catalyzed by CYP2C9,206 which, for example, include xenobiotics, the blood thinner warfarin, the anticonvulsant phenytoin, the hypoglycemic tolbutamide, and ibuprofen. In several animal models, TQ or NS treatment affected the bioavailability of prescription medications.9 This has increased relevance because culinary levels of NS intake are likely exceeded by use of dietary supplements containing seed powder and oil. Black seed/black cumin oil is available in capsules and bulk form with recommended serving sizes up to 4.6 g/d. When reported, the TQ content was 1.5% to 3.0%. Whole and ground seeds also are marketed with recommended serving sizes up to 5 g/d. These observations make it clear that care is needed in the frequent use of higher amounts of these supplements or other preparations of NS until more is known about the absorption, distribution, metabolism, and excretion of key constituents as well as their subsequent effects.

CONCLUSION

There is emerging evidence that NS can improve cardiometabolic risk factors associated with diabetes and dyslipidemia. Clinical trials provide only preliminary evidence that NS has the potential to improve neurological symptoms and respiratory disorders. Thus, more detailed quantification of TQ and other major constituents of NS extracts used in larger, high-quality clinical trials, along with the relationship of NS form, dose, and duration to clinical outcomes, is needed. Without this information, the boundaries of safe human consumption of NS and its use as a therapeutic natural product cannot be clearly defined. Until then, caution is warranted in using extracts and concentrates of NS.

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