Front. Nutr. Frontiers in Nutrition Front. Nutr. 2296-861X Frontiers Media S.A. 10.3389/fnut.2023.1107750 Nutrition Systematic Review Nigella sativa and health outcomes: An overview of systematic reviews and meta-analyses Li Zhongyu 1 2 Wang Yang 1 Xu Qing 1 Ma Jinxin 1 Li Xuan 1 Yan Jiaxing 1 Tian Yibing 1 Wen Yandong 2 * Chen Ting 1 * 1Department of Gastroenterology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China 2Department of Chinese Medicine, Eye Hospital, China Academy of Chinese Medical Sciences, Beijing, China

Edited by: Mohamed Fawzy Ramadan, Umm Al-Qura University, Saudi Arabia

Reviewed by: Waseem Khalid, Government College University, Faisalabad, Pakistan; Naina Mohamed Pakkir Maideen, Dubai Health Authority, United Arab Emirates; Mohammad Reza Khazdair, Birjand University of Medical Sciences, Iran; Reham Hamza, Zagazig University, Egypt

 *Correspondence: Yandong Wen 3180200182@caa.edu.cn Ting Chen xinglinchenting@163.com

This article was submitted to Clinical Nutrition, a section of the journal Frontiers in Nutrition

 28 03 2023 2023 10 1107750 25 11 2022 09 03 2023 Copyright © 2023 Li, Wang, Xu, Ma, Li, Yan, Tian, Wen and Chen. 2023 Li, Wang, Xu, Ma, Li, Yan, Tian, Wen and Chen

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 Background

Nigella sativa (N. sativa) consumption has been associated with various health outcomes; however, the results are not completely consistent.

 Objectives

This overview of systematic reviews and meta-analyses aimed to evaluate the reporting and methodological quality, and to grade the available evidence of associations between N. sativa and health outcomes.

 Methods

PubMed, Cochrane Library, Embase, and Scopus databases were searched from their inception to September 30, 2022. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 statement, Assessment of Multiple Systematic Reviews (AMSTAR) 2 checklist, and Grades of Recommendations, Assessment, Development and Evaluations (GRADE) systems were used to assess the reporting, methodological, and evidence quality for each meta-analysis, respectively. The results were synthesized in a narrative form.

 Results

This overview included 20 eligible meta-analyses published in peer-reviewed journals between 2013 and 2021. The overall methodological quality was relatively poor, with only one moderate quality, four low quality, and 15 critically low quality studies. For reporting quality, items two, five, eight, nine, 15, and 24 need to improve. Among the 110 outcome indicators of the quality of evidence, five were graded as moderate, 17 as low, and 88 as very low. Risk of bias, inconsistency, and imprecision were the main downgrading factors.

 Conclusion

This overview suggests that N. sativa is beneficial for various clinical outcomes. However, there are certain limitations to reporting and methodological quality. The clinical efficacy of N. sativa requires confirmation in high-quality, large-sample, randomized controlled trials.

 Nigella sativa health outcomes meta-analysis overview systematic review 1. Introduction

Nigella sativa (N. sativa) is an annual flowering plant of the Ranunculaceae family that grows widely in Middle Eastern and European countries (1). It has been used as a functional food, health product and medicine for thousands of years, suggesting that it may have some potential benefits for people (2–4). In traditional medicine, N. sativa is used for respiratory, digestive, and cardiovascular diseases, such as asthma, dyspepsia, and hypertension, and to improve liver and kidney function (5–9). Many scientific studies have demonstrated that N. sativa has a broad spectrum of positive pharmacological effects, including antiviral (10), anti-inflammatory (11), hypotensive (12), hypoglycemic (13) and antitumor (14) effects. These biological properties are related to the abundance of several phytochemicals, including thymoquinone, terpenes, saponins, flavonoids, and essential oils (8, 15). These promising active ingredients and their biological properties make N. sativa a powerful natural candidate for the prevention and control of diseases. In recent years, several meta-analyses based on randomized controlled trials (RCTs) of N. sativa have assessed its association with health outcomes. However, no review articles have evaluated the scientific quality and summarized the reported outcomes. Consequently, guidance for clinical users and physicians is limited.

Overview is a novel method for assessing the scientific quality of published systematic reviews and meta-analyses in a specific domain (16, 17). This method has been applied in many medical fields including acupuncture (18, 19), saffron (20) and dietary interventions (21). However, despite the number of systematic reviews and meta-analyses that have evaluated the association between N. sativa supplementation and health outcomes, there are no comprehensive reviews to assess the reporting and methodological quality and summarize the evidence. Therefore, the purpose of this review is to provide practical information for patients and those responsible for making treatment decisions.

 2. Methods

The current overview of meta-analyses is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2009) statement (22).

2.1. Search strategy

PubMed, Embase, Scopus, and Cochrane Library databases were searched from their inception to September 30, 2022. We used the following search strategies: (“nigella sativa” or “black cumin” or “black seed” or “black caraway” or “kalonji” or “thymoquinone”) and (“systematic review” or “meta-analysis”). No language restrictions were imposed. In addition, we manually screened the reference lists of the selected studies to identify additional studies that met the criteria. The full search strategy is listed in Supplementary Table S1. First, two independent reviewers (Y.W. and Q.X.) screened the records based on the titles and abstracts after duplicates were removed. The full texts of potentially eligible records were downloaded for further evaluation. Any disagreements were resolved by consulting a third reviewer (Y.D.W.).

 2.2. Inclusion and exclusion criteria

Articles were eligible if they were meta-analyses conducted using systematic reviews. Details of the inclusion criteria were as follows: (1) population: adults aged ≥18 years, with no restrictions on sex or race; (2) intervention: oral N. sativa intervention with any dose and treatment duration; (3) comparator: placebo, no treatment, or conventional therapy; (4) outcomes: any health outcomes, for example, blood glucose, serum lipids, liver function, etc.; and (5) study design: meta-analyses of RCTs. To clarify the therapeutic effects of N. sativa, studies on multiherbal interventions were excluded. Non-human studies, original studies, conference abstracts, and letters were also excluded. In addition, we excluded studies administrated by the topical use or injection, as these formulations have different compositions and mechanisms.

 2.3. Data extraction

Two researchers (J.X.M. and J.X.Y.) independently extracted data, including first author, year of publication, country, sample size, number of RCTs in the meta-analysis, intervention/comparation, risk of bias assessment, reported outcomes, and safety. Any disagreements were resolved by consulting a third reviewer (Y.D.W).

 2.4. Assessing the quality of included studies 2.4.1. Assessment of the reporting quality

We evaluated the reporting quality using the PRISMA 2009 statement (22). The PRISMA 2009 statement consists of 27 items in seven domains: title, abstract, introduction, methods, results, discussion, and funding. According to the reported completeness, each item was answered as “yes,” “partial yes,” or “no.”

 2.4.2. Assessment of methodological quality

We evaluated the methodological quality of the included studies using the Assessment of Multiple Systematic Reviews (AMSTAR) 2 checklist (23). The AMSTAR-2 checklist consists of 16 items, and each item could be answered as “yes,” “partial yes” or “no.” The overall methodological quality of each study was then classified as “high,” “moderate,” “low” or “critically low.”

 2.4.3. Grading the evidence quality

We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system to assess evidence quality (24), which includes five domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias. And the quality of evidence for each outcome was graded as “high,” “moderate,” “low” and “very low.”

Two researchers (X. L. and Y. B. T.) independently assessed the reporting, methodological, and quality of evidence. Any disagreements were resolved by consulting a third researcher (T.C.).

 2.5. Statistical analysis

The efficacy and safety results reported in the included meta-analyses with N. sativa were synthesized in a narrative review, including risk ratio (RR), odds ratio (OR), mean difference (MD), weighted mean difference (WMD), and standard mean difference (SMD), along with P-value and a 95% confidence interval (CI). I2 was used to test for heterogeneity. In addition, we calculated compliance rates for PRISMA 2009 statement and AMSTAR 2 checklist item in meta-analyses, and reported the number and percentage of “yes,” “partial yes” or “no” responses. The reporting and methodological quality were visualized using a radar plot and bar chart, respectively. According to a previous study, a percentage of “yes” < 60% for an item indicates a need for improvement (25). Excel 2016 (Microsoft Corporation, WA, USA) was used for data analysis and visualization.

 3. Results 3.1. Literature search results

Our initial search identified 436 potential records. After removing duplicates, a total of 244 records remained. Subsequently, 210 records were excluded after screening titles and abstracts. The full texts of 34 records were further evaluated, and 20 records (26–45) were eventually included in the analysis (Figure 1 shows the flow chart of study selection).

PRISMA flow chart for the included studies.

 3.2. Basic characteristics of the included literature

All meta-analyses were published in peer-reviewed journals between 2016 and 2022. These studies were conducted in seven regions: 13 from Iran (28, 30, 33, 34, 37–45), two from China (32, 35), and one each from Australia (26), India (27), United Kingdom (29), the USA (31), and Indonesia (36). The number of RCTs ranged from three to 50, with 187–3,679 subjects. Most studies have reported forms of N. sativa, including capsules, oils, and powders. Nineteen studies reported doses of N. sativa, ranging from 0.5 to 6 g or 2.5 to 5 ml daily (26–30, 32–45). Five studies reported the frequency of N. sativa administration, which varied between once, twice, and thrice a day (29, 32–35). The treatment duration ranged from 2 weeks to 1 year. Four studies registered protocols on the PROSER platform (27–29, 39) and one in the Cochrane library (31). In terms of the risk of bias tools, 10 studies used the Cochrane risk of bias tool (26–28, 30, 31, 33, 35, 39, 44, 45), nine studies used the Jadad scale (32, 34, 36–38, 40–43), and one used the standardized JBI critical appraisal checklist (29). Table 1 summarizes the basic characteristics of the included meta-analyses.

Characteristics of the included studies.

Reference Country Health status Interventions/ comparations Number of primary studies Sample size (I/C) Dose Frequency Form Duration Registration information Bias of risk assessment Reported outcomes Safety
Saeede Saadati (26) Australia Prediabetes and T2DM N. sativa /Placebo, routine therapies 11 666 (338/328) 0.9 to 5 g/day NR Oil = 9; Ext = 2 2–6 months No Cochrane BMI, FPG, OGTT, HbA1c, fasting insulin, HOMA-IR, TG, TC, LDL-C, HDL-C, CRP, and MDA No
Anoop Tiwari (27) India NAFLD N. sativa / Placebo 4 224 (NR) 1,000 to 2,000 mg/day NR Cap = 2; Oil = 2 8–12 weeks PROSPERO (CRD42020179378) Cochrane ALT, AST, TG, LDL-C, HDL-C, BMI No
Sahar Golpour-hamedani (28) Iran Adults (Dyslipidemia = 2; Mets = 4; Obesity = 3; Hypertension = 4; Healthy volunteer = 4; Menopausal women = 1; PCOS = 1; T2DM = 1; Cardiovascular diseases = 1; NAFLD = 1) N. sativa / Placebo, standard therapy 22 1208 Pow: 500 to 1,000 mg/day; Cap: 400 to 2,000 mg/day; Oil: 3 to 5 ml/day NR Pow = 5; Cap = 12; Oil = 4; NR = 1 3 weeks to 1 year PROSPERO (CRD42022315493) Cochrane SBP, DBP No
Kaushik Chattopadhyay, (29) United Kingdom T2DM N. sativa/ Placebo, conventional therapy, no treatment 8 NR Cap: 0.5 to 3g/day; Oil: 5 ml/day Qd = 1; Bid = 5; TID = 2 Cap = 7; Oil = 1 8–13 weeks PROSPERO (CRD42018118285) Standardized JBI critical appraisal checklist FPG, PPBG, HbA1c, fasting insulin, HOMA-IR, BMI, BW, TG, TC, LDL-C, HDL-C Yes
Neda Azizi (30) Iran Adults (NAFLD = 4; T2DM = 1; Postmenopausal women with osteoporosis = 1; obese = 1; hypercholesterolemia = 1) N. sativa/Placebo 8 519 (281/279) Oil:2.5 to 3 ml; Cap:0.5 to 1 g Bid = 1; Tid = 1; NR = 6 Cap = 4; Oil = 4 6–12 weeks No Cochrane AST, ALT No
Dinesh Gyawali (31) USA Hypercholesterolemia N. sativa/Placebo 3 NR NR NR NR 4–8 weeks Cochrane Database Cochrane TC, TG, HDL, LDL No
Anqiang Han (32) China Asthma N. sativa/Placebo 4 187 (NR) 0.5–1 g Bid=1; NR=3 Cap=3; Ext=1 4 weeks to 3 months No Jadad scale ACT, FEV1, PEF, IL-4, IFN-γ No
Sanaz Malekian (33) Iran Adults (Obesity = 3; RA = 2; T2DM = 2; Mets = 1; UC = 1; NAFLD = 2) N. sativa/Placebo 11 710 (NR) 0.5–3 g/day Bid=3; Tid=3; Qd=2; Qid=3 Cap=11 6 weeks to 1 year No Cochrane TNF-α, hs-CRP, IL-6, SOD, TAC, MDA Yes
Rahele Sadat Montazeri (34) Iran Adults (Obesity = 2; RA = 2; T2DM = 2; Mets = 2; UC = 1; NAFLD = 1) N. sativa/Placebo 10 630 (NR) 1–3g/day NR NR 6–48 weeks No Jadad scale hs-CRP, TNF-α, MDA, TAC, SOD NR
Gang Tang (35) China NAFLD N. sativa/Placebo 5 358 (179/179) Cap: 75 mg to 2 g/day; Oil: 5 ml/day Bid = 2; Tid = 1; NR = 2 Oli = 2; Cap = 3 8–24 weeks No Cochrane ALT, AST, insulin, FBS, TC, TG, HDL, LDL, hs-CRP, TNF-α, grade of fatty liver Yes
M.Ardiana (36) Indonesia Adults (Obese = 1; RA = 1; T2DM = 2; UC = 1) N. sativa/Placebo 5 293 (152/141) 500 mg−3g/day NR Cap = 5 8–48 weeks No Jadad scale MDA, SOD, TAC NR
Jamal Hallajzadeh (37) Iran Adults (T2DM = 12; Mild hypertension = 2; Insulin resistance = 1; Overweight or obesity = 7; Mets = 9; RA = 2; UC = 1; NAFLD = 4; Dyslipidemia = 6; Healthy volunteer = 4; Menopausal women = 2; HT = 1; kidney disease = 1; other disease = 5) N. sativa /Placebo 50 3,679 (1,932/ 1,747) Cap: 400–3,000 mg/day; Oil: 2.5–5 ml/day; Pow: 400 to 3,000 mg/day; Ext: 700 mg/day NR Oil = 19; Pow = 11; Cap = 13; Ext = 2; NR = 12 2–12 months No Jadad scale TC, TG, LDL-C, VLDL-C, HDL-C, FBS, HbA1C, Insulin, HOMA-IR, CRP, TNF-α, MDA, TAC NR
Mohsen Mohit (38) Iran Adults (T2DM = 3; RA = 2; NAFLD = 2; UC = 1; Obese = 2; HT = 1; Helicobacter infected patients = 1) N. sativa/Placebo 12 659 (339/320) 1–3 g/day NR Cap = 10; Pow = 2 6–48 weeks No Jadad scale TAC, MDA, TNF-α, IL-6, CRP NR
Elham Razmpoosh (39) Iran Adults (Stable angina = 1; Hypertension = 2; Kidney disease = 2; T2DM = 2; Obese = 3; Liver diseases = 2; Healthy individuals = 4; Osteoporosis = 1; Hypercholesterolemia = 1; Menopause women = 1) N. sativa or black seed family/Placebo 19 1,295 0.5–6 g/day NR Oil = 12; Pow = 7 4–42 weeks PROSPERO (CRD42018102229) Cochrane ALT, AST, ALP, BUN, CREA, uric acid, bilirubin, urine, serum total protein, albumin NR
Rahele Tavakoly (40) Iran Adults (Mets = 2; Obese = 2; RA = 1; UC = 1; NAFLD = 1) N. sativa/Placebo 7 439 (222/217) 1–3 g/day NR Oil = 2; Pow = 5 6–12 weeks No Jadad scale Serum CRP NR
Seyed Mohammad Mousavi (41) Iran Adults (T2DM = 2; Hypertension = 1; Hypercholesterolemia = 1; HT = 1; NAFLD = 1; Obesity and overweight = 3; Healthy subjects = 4) N. sativa/Placebo 13 875 (445/430) Oil: 5 ml/day or 3 g/day; Cap: 100 mg to 2 g/day NR Oil = 4; Cap = 9 6–13 weeks No Jadad Score BW, BMI, WC NR
Nazli Namazi (42) Iran Adults (Overweight/obesity = 3; Diabetes = 2; Mets = 2; Hypertension = 1; RA = 1; Healthy subjects = 2) N. sativa/Placebo 11 783(NR) Pow: 1 to 2 g/day; Oil: 3 to 5g/day; Ext: 100 to 200mg/day NR Pow = 5; oil = 5; Ext = 1 6–12 weeks No Jadad scale BW, BMI, WC Yes
Reza Daryabeygi-Khotbehsara (43) Iran T2DM N. sativa/Placebo or standard treatment 7 555 (255/250) 0.5 to 2g/day NR Pow = 4; Oil = 3 2 to 12 months No NO FBS, HbA1c, TC, TG, HDL, LDL NR
Amirhossein Sahebkar (44) Iran Adults (Mets = 2; Overweight/obesity = 3; Hypertension = 1; Hyperlipidemia = 5; T2DM = 3; Menopausal women = 3; Healthy subjects = 2) N. sativa/Placebo 17 1185 (619/569) Pow: 1 to 2 g/day; Oil: 100 mg to 3g/day or 5 ml/day NR Pow = 10; Oil = 7 4 weeks to 3months No Cochrane TC, LDL-C, HDL-C, TG NR
Amirhossein Sahebkar (45) Iran Adults (Healthy subjects = 3; Mets = 2; Hypertension = 1; Hypercholesterolemia = 1; Menopausal women = 1; Perimenopausal women = 1; Obese = 2) N. sativa/Placebo or standard treatment 11 860 (435/425) Pow: 500 mg to 2 g/day; Oil: 200 mg to 3 g/day or 5 ml/day NR Pow = 8; Oil = 3 4–12 weeks No Cochrane BP, DBP Yes

T2DM, type 2 diabetes mellitus; Mets, metabolic syndrome; NAFLD, non-alcoholic fatty liver diseases; RA, arthritis rheumatoid; Mets, metabolic syndrome; UC, ulcerative colitis; HT, Hashimoto's thyroiditis; pow, Power; ext, extract; cap, capsule; BMI, Body Mass Index; FPG, fasting plasma glucose; OGTT, oral glucose tolerance test; HbA1c, hemoglobin A1c; HOMA-IR, homeostatic model assessment of insulin resistance; TG, triglyceride; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; CRP, C-reactive protein; CREA, Creatinine; MDA, malondialdehyde; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; FBG, fasting blood glucose; PPBG, postprandial blood glucose; BW, body weight; ACT, asthma control test; FEV1, forced expiratory volume at 1s; PEF, peak expiratory flow; IL-4, interlukin-4; IFN-γ, interferon γ; TNF-α, tumor necrosis factor-α; hs-CRP, high-sensitive C-Reactive Protein; IL-6, interlukin-6; SOD, superoxide dismutase; TAC total antioxidant capacity; VLDL, very low-density lipoproteins; BUN, blood urea nitrogen; SBP, systolic blood pressure; DBP, diastolic blood pressure.

 3.3. Results of reporting quality

According to the PRISMA 2009 statement, 20 of the 27 items had a “yes” response rate of more than 60%, indicating that the included meta-analyses contained relatively complete reporting quality. However, there were limitations related to the following items: item two (abstract: structured abstract), five (method: protocol and registration), eight (method: search), nine (method: study selection), 17 (result: study selection), 22 (result: risk of bias across studies), and 24 (discussion: summary evidence) (see Figure 2 and Supplementary Table S2).

Reporting quality of included meta-analyses based on the PRISMA 2009 statement.

 3.4. Results of methodological quality

The results of the overall methodological quality evaluated using the AMSTAR-2 checklist revealed that only one study was of moderate quality, four studies were of low quality, and the other 15 meta-analyses were of critically low quality (Supplementary Table S3). Methodological quality limitations included the following items: item two (register protocol prior to conducting the review), three (explain selection of the study designs in the review), seven (provide a list of excluded studies and justify the exclusions), and 10 (report the source of funding for the individual studies) (see Figure 3 and Supplementary Table S3).

Methodological quality of included meta-analyses based on the AMSTAR-2 checklist.

 3.5. Results of the quality of evidence

There were 110 outcome indicators in 20 meta-analyses. Five were graded as moderate-quality, 17 as low-quality, and 88 as very-low-quality evidence. However, there is no high-quality evidence for this. The evidence was mostly downgraded owing to the risk of bias, inconsistency, and imprecision (Supplementary Table S4).

 3.6. Therapeutic effect of <italic>N. sativa</italic> on health outcomes 3.6.1. Blood glucose and insulin secretion

Four studies evaluated the effects of N. sativa on glucose metabolism and insulin function (26, 29, 37, 43). All studies found that N. sativa reduced hemoglobin A1c (26, 29, 37, 43). Three studies observed that the consumption of N. sativa reduced fasting plasma glucose (FPG) levels (26, 37, 43), but one study found N. sativa had no effect on FPG in type-2 diabetes (29). In addition, N. sativa had no significant effect on the oral glucose tolerance test (OGTT) (26), fasting insulin levels (26, 29), homeostasis model assessment of insulin resistance (HOMA-IR) (26, 29, 37) and postprandial blood glucose (PPBG) (29).

 3.6.2. Serum lipids

Eight studies evaluated the effects of N. sativa on lipid profiles (26, 27, 29, 31, 35, 37, 43, 45). Six studies found that N. sativa reduced total cholesterol (TC) in patients with metabolic disorders (26, 29, 31, 37, 43, 45), but one study showed that N. sativa had no effect on patients with non-alcoholic fatty liver disease (NAFLD) (35). Seven studies found that N. sativa significantly reduced triglyceride (TG) levels (27, 29, 31, 37, 45), although four studies revealed that it did not change TG levels (26, 31, 35, 43). Six studies found that N. sativa reduced low-density lipoprotein cholesterol (LDL-C) levels (26, 27, 29, 37, 43, 45), drawing consistent conclusions. Only one study showed a significant effect on high-density lipoprotein cholesterol (HDL-C) levels (27), whereas the remaining five studies found that N. sativa did not change HDL-C levels (26, 29, 31, 43, 45).

 3.6.3. Blood pressure

Two studies evaluated the effects of N. sativa on blood pressure (28, 45). The results showed that N. sativa significantly reduced systolic and diastolic blood pressure in adults (28, 45).

 3.6.4. Body composition

Five studies evaluated the effects of N. sativa on body parameters (26, 27, 29, 41, 42). Three studies reported that N. sativa significantly reduced body weight (BW) (29, 41, 42). Two studies observed that N. sativa significantly reduced the body mass index (BMI) (41, 42), however, three studies found no effect on BMI (26, 27, 29). One study showed that N. sativa reduced waist circumference (WC) (42), but another showed no effect on WC (41).

 3.6.5. Inflammatory markers

Eight studies evaluated the effects of N. sativa on inflammatory markers (26, 32–35, 37, 38, 40). In adults, studies have observed that N. sativa intake significantly reduced tumor necrosis factor-α (TNF-α) (26, 33, 34), high-sensitivity C-reactive protein (hs-CRP) (34, 35), interleukin-6 (IL-6) (33), and C-reactive protein (CRP) (38, 40). However, other meta-analyses have shown that N. sativa supplementation had no effect on TNF-α (37, 38), hs-CRP (33), IL-6 (33), and CRP (37). In addition, one study observed that consumption N. sativa decreased interleukin-4 and increased interferon-γ in patients with asthma, but the difference was not statistically significant (32).

 3.6.6. Oxidative stress factors

Six studies evaluated the effects of N. sativa on oxidative stress factors (26, 33, 34, 36–38). However, these results were contradictory. In adults, studies have shown that N. sativa reduced malondialdehyde (MDA) (26, 34, 38) and increased superoxide dismutase (SOD) (33, 34, 36) and total antioxidant capacity (TAC) (33, 34, 38). The remaining meta-analyses found that N. sativa had no significant effects on MDA (33, 36, 37) and TAC (36, 37).

 3.6.7. Asthma

One study evaluated the effects of N. sativa on asthma (32). The results showed that N. sativa supplementation improved asthma control test scores and forced expiratory volume at 1s in patients with asthma, however, it had no significant effect on peak expiratory flow (32).

 3.6.8. Liver and kidney parameters

Four studies evaluated the effects of N. sativa on liver parameters (27, 30, 35, 39) and one study evaluated kidney parameters (30). One study found that N. sativa significantly improves fatty liver grading in patients with NAFLD (35). Three studies reported that N. sativa reduced aspartate aminotransferase (AST) levels (27, 30, 35). However, one study reported that N. sativa failed to reduce AST levels (39). Two studies found N. sativa reduced alanine aminotransferase (ALT) levels (27, 35), whereas two other studies found N. sativa had no effect on ALT levels (30, 39). In addition, one study observed that the use of N. sativa significantly reduced the alkaline phosphatase levels (39). In terms of kidney parameters, N. sativa significantly reduced urea nitrogen, but had no effect on creatinine, bilirubin, and uric acid levels (30).

 3.6.9. Safety

Five meta-analyses reported adverse events (29, 33, 35, 42, 45). The main adverse events were digestive symptoms such as stomach pain, diarrhea, nausea, and vomiting, as well as weakness and weight loss. However, no study has reported serious adverse events.

 4. Discussion

In recent years, plant-based foods and herbs as therapeutic alternatives, have received a great deal of attention from both researchers and the general public (46, 47). Medicinal plants can be used for the treatment and prevention of various non-communicable diseases because they contain a wide range of bioactive phytochemicals and have different metabolic effects (48, 49). This is the first overview to synthesize the available meta-analyses for N. sativa and evaluate the reporting, methodological, and evidence quality. We found that N. sativa has a variety of potential effects on different indicators in clinical practice, including blood glucose, inflammatory markers, oxidative stress factors, serum lipids, blood pressure, liver and kidney parameters, and even asthma indicators. The therapeutic effects suggested that N. sativa has beneficial effects in various diseases and may be a promising complementary and alternative therapy.

The overall reporting quality of the meta-analyses was poor, highlighting the importance of future reviews to improve the standards. Regarding the PRISMA 2009 statement, items two, five, eight, nine, 17, 22, and 24 need significant improvement. In recent years, the problem of reproducibility and the waste of resources in biomedical research have caused considerable concern in the scientific community (50, 51). However, comprehensive and transparent reporting of the study design, study process, and final outcomes is key to avoiding these problems. Therefore, we strongly recommend that future meta-analyses of N. sativa should be performed in accordance with the PRISMA statement.

In terms of methodological quality, we found that items two, three, seven and 10 should be improved based on the AMSTAR-2 checklist. The registration of protocols can improve the transparency and help avoid the potential risk of bias (52, 53). It can also reduce duplicate work between different research groups and continue studies to date (54). The authors are encouraged to register their protocols in free and open databases, such as the PROSPERO platform and Cochrane Library, to avoid study bias (55). The AMSTAR-2 checklist requires review authors to explain why they chose a particular study design for meta-analysis (23), as systematic reviews should be “comprehensive” and specific study designs should be selected for different purposes. Furthermore, a comprehensive literature search strategy is the basis and a guarantee of meta-analysis. This helps to avoid missing data, leading to selective bias and obtaining the correct conclusions (56). In addition, the authors are required provide a full list of excluded studies and justify their exclusions, which can help the readers judge the extent of study inclusion and the accuracy of manuscript selection. Finally, the authors should clearly report a statement about funding sources and conflicts of interest. This can help other researchers judge the reliability of the conclusion and prevent bias that might favor funders (57). For example, authors may present favorable results and/or exaggerate the effects of drugs provided by industry funders (58). Therefore, the use of rigorous methodology reduces the risk of bias and improves the reliability of the conclusions.

The findings from the included meta-analyses suggested that N. sativa has potential efficacy in treating various diseases. However, according to the GRADE system, we found only five moderate quality, 17 low quality, and 88 very low quality studies, with an overall poor quality of evidence. The highest downgrading factor was the risk of bias. This was mainly due to RCTs with unclear or missing randomization, blinding, and allocation concealment. Therefore, in future studies, designers should pay more attention to the design and implementation processes. Another downgrading factor was inconsistency, with most studies showing high heterogeneity (I2 > 50%). This may be related to the different subjects, multiple forms of N. sativa supplements, and treatment duration. Future meta-analyses should explore potential heterogeneity based on subgroup, meta-regression, and sensitivity analyses. It is important for researchers to report in detail on the bioactive constituents of N. sativa and to transparently report on the N. sativa species, the dose and frequency of intervention administration, treatment duration, and adherence. Although most meta-analyses have provided certainty about the clinical efficacy of N. sativa, the overall sample size was low, suggesting that there remains a need for clinical evidence from high-quality, large-sample RCTs.

4.1. Strengths and limitations

This overview has several strengths and limitations. Regarding the strengths, this is the first overview to comprehensively summarize the clinical evidence of N. sativa supplementation and provide visualization of reporting and methodological quality. The results make up the knowledge gap regarding N. sativa supplements and can be used to guide further research and clinical decision-making. This study has several limitations. First, this overview only used a descriptive method, making it difficult to evaluate primary studies. Second, although two researchers who have been trained and passed the pre-test, independently conducted literature screening and quality evaluation, subjective factors cannot be eliminated and may affect objectivity. Third, because most studies did not mention adverse events, it is difficult to accurately assess the safety of N. sativa in clinical practice.

 5. Conclusion

This overview suggests that N. sativa has the potential to improve different clinical outcomes, such as blood glucose, inflammatory markers, oxidative stress factors, serum lipids, blood pressure, liver and kidney parameters, and even asthma indicators. However, there are certain limitations in reporting and methodological quality, and future studies should improve the administration process. In addition, the clinical efficacy of N. sativa needs to be confirmed in high-quality, large-sample RCTs to generate more evidence-based clinical practice.

 Data availability statement

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

 Author contributions

ZL designed and drafted the manuscript. YW, QX, JM, JY, XL, and YT performed the literature search, extracted the data, and assessed their quality. ZL, TC, and YW analyzed and interpreted the data. All the authors participated in this study and reviewed and agreed to publish this article.

 Funding

This study was supported by the National Natural Science Foundation of China (No. 82074420) and Scientific and Technological Innovation Project of the China Academy of Chinese Medical Sciences (CI2021A01005).

We would like to thank all authors who contributed to this review.

 Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Publisher's note

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