Clinical Uses of Nigella Sativa in Pediatrics: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Introduction

The benefits of Nigella sativa (NS) have attracted considerable research attention due to its immunomodulatory, anti-inflammatory, and antioxidant properties. NS use has been widespread in traditional medicine throughout history, especially in Prophetic Medicine (Tibb-e-Nabwi), Unani, Siddha, and Ayurveda. The oil and seeds of this plant have been used in folklore as medicines and foods; it is considered one of the most effective healing methods in Islamic literature.¹ Nigella sativa is a medicinal herb belonging to the Ranunculaceae family and widely referred to as blackseed, also called black cumin or kalonji. The seeds and oils of NS contain various bioactive components, such as thymoquinone, thymohydroquinone, and carvacrol.² Thymoquinone is a major bioactive component of NS, identified as a potential antimicrobial, anti-inflammatory, and chemoprotective agent.¹

Nigella sativa is native to several regions, including Southwest Asia, the Eastern Mediterranean, North Africa, and Asia, and has been used in numerous food cultures as a flavoring agent and adjuvant.³ Nigella sativa comprises 38% to 45% lipids, 32% carbohydrate, and 21% protein; primary amino acids found in it are glutamic acid, aspartic acid, arginine, leucine, and glycine. It contains high levels of unsaturated fatty acids (57.71% linoleic acid and 24.46% oleic acid), mainly in Nigella sativa oil (NSO). The oil in NS seeds is rich in essential fatty acids, tocopherols, phytosterols, and polyphenols, making it a valuable ingredient in traditional medicine and the food industry.⁴ The seeds of NS are rich in calcium, magnesium, sodium, potassium, phosphorus, manganese, iron, zinc, and copper.⁵ Research has examined the plant’s potential benefits for diabetes mellitus, skin cancer, acne vulgaris, and wound healing.² Furthermore, the plant has been shown to benefit the reproductive, pulmonary, and immune system.¹ Gholamnezhad et al⁶ reviewed numerous studies showing that NS and its main active compound, thymoquinone, have anti-inflammatory, antioxidant, antimicrobial, antitumor, antidiabetic, and antiepileptic properties that could benefit children. Nigella sativa and thymoquinone have glucose-lowering effects that could help manage diabetes in children and hepatoprotective effects that could prevent damage to liver tissue in children exposed to toxic substances.⁷ In addition, NS and thymoquinone have been found to possess immunomodulatory effects that could strengthen the immune system. Additionally, it has a bronchodilator effect that could benefit children with asthma and allergies.^6,8 However, the safety of using NS in the pediatric population is unclear. Mashayekhi et al⁹ investigated the toxicological profile of NS and reported that it is generally considered safe, but more detailed studies are needed to draw a definitive conclusion. The side effects of this medicinal herb did not cause serious adverse events, and it can be used in clinical trials because of its major effects that have been shown to be beneficial.¹⁰ To our knowledge, no systematic review has been conducted to evaluate the efficacy, safety, and clinical uses of NS in pediatrics. Therefore, this systematic review aims to assess the safety, effectiveness, and clinical uses of NS in the pediatric population.

Materials and Methods

Search Strategies.

This systematic review follows the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. It is registered in the International Prospective Register of Systematic Reviews (PROSPERO ID: CRD42023475329).

A search was conducted across 4 databases for studies published until September 6, 2023. PubMed, Cochrane, Web of Science, and Scopus (Elsevier) databases were systematically searched for relevant English-language studies published in the literature. Search terms used were “Nigella Sativa” OR “black seed” OR “black cumin” OR “kalonji” AND “pediatric*” OR “child*” OR “adolescen*” (Table 1). No filter was used in the Web of Science and Scopus databases. The clinical trials filter was used in PubMed and Cochrane. The search was peer-reviewed by another independent reviewer. No date limits were applied. The criteria included clinical trials, studies on children/pediatric populations, and studies in the English language. Exclusion criteria included review papers, case studies, non-English language studies, studies on adults, irrelevant studies, studies that did not use NS, and studies published without full articles. Randomized control trials (RCTs) were considered eligible if they answered the following questions of the P-I-C-O-S model:

Table 1.Search Strategy

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P: Participants: pediatric patients.

I: Intervention: using NS.

C: Comparator: compared with standard treatment or others.

O: Outcomes: outcomes measured by the study (no specific outcome).

S: Study design: RCT.

Results

Literature Search and Study Characteristics.

Two hundred sixty-five studies were screened for eligibility; 125 papers from Scopus, 31 from PubMed, 37 from Cochrane, and 72 from the Web of Science. Sixty-eight duplicate papers were eliminated, and 185 studies were excluded. Reasons for excluding records were review papers (n = 22), studies on adults (n = 17), animal studies (n = 23), irrelevant studies (n = 100), nonclinical trials (n = 11), studies without full articles (n = 6), not using NS (n = 3), still conducting the study (n = 3). Studies that might meet the inclusion criteria but were excluded because of the study design.¹⁰ Three studies were identified from 383 papers obtained through backward and forward (snowballing) citations. Fifteen clinical trial studies were included in this review, as depicted in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram in Figure 1. The summary of the included studies is displayed in Table 2. All studies were published between 2008 and 2020. Four studies were conducted in Egypt, 4 in Iran, 2 in Iraq, 2 in Indonesia, 1 in India, 1 in Pakistan, and 1 in Bangladesh.

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Table 2.Summary of Included Studies

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NS Forms, Doses, and Side Effects.

Different forms of NS have been used to treat various diseases in children, such as natural seeds, aqueous extract, powdered form, oil, topical lotion, and nasal drops. Doses included oral powdered NS at a dose of 500 mg/day for 4 weeks up to 2 g/day for 3 months or based on body weight at a dose of 40 mg/kg in 2 equally divided doses for 3 months, with no side effects reported in those studies. One study used whole natural NS seeds at a dose of 5 g/day for 3 to 9 months with no side effects or adverse events reported.¹⁸ Oil of NS was used at a dose of 15 to 30 mL/kg/day for 8 weeks, with no side effects reported, and at a dose up to 40 to 80 mg/kg/day for 4 weeks.^19,26 Nausea and vomiting were reported in 1 patient, and 2 patients had an exacerbation of seizures after receiving NS oil.⁷ Topical NS in the form of skin lotion or hydrogel has been used to treat pustule infection and acne,^21–23 or as nasal drops at approximately 15 mL, 2 drops (1 in each nostril) administered 3 times/day for 6 weeks to treat allergic rhinitis.²³ A summary of the doses, forms, and side effects reported by each study has been described in Tables 3 and 4. None of the studies reported a severe adverse event, and a few reported mild side effects.

Table 3.Summary of the Reported Side Effects From Using Oral Nigella Sativa

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Table 4.Summary of the Reported Side Effects From Using Topical Nigella Sativa

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Table 5.Nigella Sativa and Children With Epilepsy

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Quality Assessment and Risk of Bias.

All included studies in the review were available in full text. The overall risk of bias across 15 studies was assessed; 4 had a low risk of bias, 1 had some concerns, and the remaining 10 RCTs had a high risk of bias, as shown in Figure 2. Despite this, we reported a low risk of bias concerning the randomization process (73% low risk). Some studies did not clearly describe the type of randomization process. The domain of deviations from the intended intervention had a 50% high risk of bias due to the lack of double blinding in most of the studies or blinding not being mentioned in the study.

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Furthermore, almost none of the included studies have evaluated adherence to the intervention. Low risk of bias was judged regarding the domain of missing outcome data for all studies. However, most of the included studies reported a high risk of bias in the domain of measuring the outcome, with only 40% of studies having a low risk of bias. Finally, only 13% have a high risk of bias in the domain of selecting reported results, and most of the studies included showed a low risk of bias in this domain.

Statistical Analysis.

Meta-analysis of the pooled data is shown in Figure 3. Of the 114 participants in the NS group, 12 reported side effects, compared with 102 participants in the placebo group, with only 3 experiencing side effects. Overall, the analysis shows that the reported side effects in the included studies are statistically not significant, as indicated by a p value > 0.05. No heterogeneity exists between studies (I² = 0%). For the efficacy of using NS in pediatrics, meta-analysis was applicable only to 3 studies conducted on children with epilepsy. The meta-analysis was pooled from 3 studies, which could generate the OR and CI to evaluate the efficacy of using NS in epilepsy (seizure frequency). As shown in Figure 4, the effect of NS on seizure frequency was not significant (p value > 0.05). No heterogeneity exists among the 3 studies, with an I² value of 0%. The risk of bias summary is presented in Figures 5 and 6. The symmetrical distribution of the points and their scatter suggests that there is a publication bias in both meta-analyses, due to the small number of studies included in the meta-analyses.

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Discussion

Nigella sativa’s immunomodulatory, anti-inflammatory, and antioxidant properties have been observed in many clinical trials. However, few studies have been conducted on the pediatric population. Three studies in this review have evaluated the efficacy of NS in children with epilepsy (Table 2).^13,14,27 Shawki et al¹⁴ evaluated the efficacy of black seed oil at a dose of 40 to 80 mg/kg/day for 4 weeks. They reported that black seed oil did not significantly affect seizure frequency or severity. In addition, the study reported an exacerbation of seizures after receiving black seed oil in 2 patients. However, a greater than 50% reduction in seizure frequency was seen in 6 patients. A greater than 50% reduction in the severity of seizures was seen in 2 patients after the administration of black seed oil in the study by Noor et al.²⁸ Momen and colleagues¹³ showed that using a mixture of NS and Thymus vulgaris extracts (Epistop) for 8 weeks does not affect the duration and frequency of seizures. However, 4 children with refractory epilepsy showed a significant reduction in seizure frequency after administration of Epistop. The author’s opinion was that the administration of the Epistop might be beneficial in children with refractory seizures with typical development, normal magnetic resonance imaging and electroencephalogram, and low seizure frequency of less than 10 events per week. Using the aqueous extract of NS seeds in a dose of 40 mg/kg/8hr for 4 weeks was effective and had an antiepileptic effect in children with refractory epilepsy.¹⁴ The benefits seen in epileptic patients included in those studies might be due to the thymoquinone presented in NS, which produces antinociceptive effects through indirect activation of the supraspinal mu (1)- and kappa-opioid receptor subtypes. Thymoquinone had anticonvulsant activity in rats, probably through an opioid receptor-mediated increase in GABAergic tone.²⁹ Almost all animal studies that have explored the effect of NS on seizure models have shown an anticonvulsive effect.^29–33

In the current review, 2 studies have investigated the anti-asthmatic effect of NSO in asthmatic children,^19,26 and 1 study evaluates the role of NSO in wheeze-associated lower respiratory tract illness in children (Table 2).²⁰ Supplementation with NSO at a dose of 15 to 30 mg/kg/day with standard treatment for 8 weeks was compelling and improved interferon-g/interleukin-4 balance, T-helper cell 17/Treg balance, asthma control score, and symptoms in asthmatic children. The chemical composition of NS has been studied in detail. One of the main active components appears to be mainly attributed to thymoquinone. The mechanism of action of NS enables it to act as an immunomodulator and regulate T helper/Treg balance.³⁴ Boskabady and Farhadi³⁵ have reported a beneficial effect of using the aqueous extract of NS as a prophylactic measure to improve the asthma severity. Another study has shown that NSO helps decrease pulmonary index and increase peak expiratory flow rate in children with wheeze-associated lower respiratory tract illness.²⁰ Nigella sativa is therapeutically beneficial in controlling asthma symptoms and relieving airway inflammation.³⁶

Three studies were conducted on children with leukemia and 1 on children with brain tumors. A review of NS and its anti-cancer properties in vitro and in vivo models found that this might be due to the high thymoquinone content in NS.³⁷ Nigella sativa has been shown to possess antineoplastic activity against tumors.³⁸ Nigella sativa exhibits an anti-cancer effect through different proposed mechanisms of action, including its effect on the activity of enzymes, usage of free radicals, intracellular glutathione changes, inhibiting cell proliferation, trapping the free radicals, and antioxidant activity.^39,40 All 3 studies in this review were focused on reducing treatment or disease-related side effects.

Dogar et al¹⁵ reported that NS seeds, at a dose of 40 mg/kg/day in 2 equally divided doses for 3 months, in combination with a cytotoxic drug, could assist in the treatment of acute lymphoblastic leukemia. It significantly improved treatment outcomes and proved to be an excellent anticancer agent. The 2 studies from Hagag and colleagues^16,17 reported an improvement in some cardiac side effects of doxorubicin in children with ALL (n = 40), exhibiting better systolic function, as well as decreased methotrexate hepatotoxicity, and improved overall survival. Mousa et al¹⁸ used whole natural black seeds at a dose of 5 g/day for 3 to 9 months to decrease the incidence of febrile neutropenia and length of hospital stay in children with brain tumors (n = 80).

The current review also included 2 studies on acne vulgaris patients^21,22 and 1 on newborns with a staphylococcal skin infection (Table 2).²⁴ A 10% NS oil lotion applied twice daily for 8 weeks was a safe and well-tolerated topical therapy for acne vulgaris.²² Thymoquinone, the active component in NS, has been shown to suppress leukotrienes, prostaglandins, and 5-lipoxygenases in numerous inflammatory models and can also decrease the production of IL-1β, TNF-α, and monocyte chemoattractant protein.^34,41 Nitric oxide production in macrophages and mixed-glial cells is reduced by the NS extract and thymoquinone lipopolysaccharide-induced inflammation.^41,42 The aqueous extract of NS can suppress the expression of key inflammatory mediators, including nitric oxide, IL-6, and tumor necrosis factor.³⁷ Nigella sativa has anti-bacterial effects against many bacteria, and multidrug-resistant strains, such as Staphylococcus aureus and Mycobacterium tuberculosis. NS is active against several bacteria, including Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. Alpha-pinene, one of the phytochemicals in NS, impacts Propionibacterium acnes.⁴³

Additionally, Soleymani et al²¹ showed that applying a topical NS hydrogel twice a day for 60 days reduced the symptoms of acne vulgaris when used topically 3 times a day for 4 days on skin lesions in newborns and infants aged 6 to 11 days.

Black seed extract drops were found to have antibacterial activity and to be as effective as the usual medication, mupirocin, in treating localized infections. Nigella sativa is thought to have potential as a medicinal plant for treating acne due to its immunomodulatory, anti-inflammatory, antioxidant, and antibacterial properties against P. acne. Other clinical uses of NS in pediatrics were used on children with beta-thalassemia major (n = 25); 2 g/day of powdered NS added to foods or drinks for 3 consecutive months was found to decrease iron overload-induced oxidative stress and hemolytic anemia. In addition, NS reduced the side effects of iron chelation therapy.⁴⁴ Nigella sativa was also used in patients suffering from allergic rhinitis as a topical oil (nasal drops) of approximately 15 mL, 2 drops (1 in each nostril) 3 times/day for 6 weeks; it improved the symptoms and was effective in the treatment of allergic rhinitis, and only nasal dryness was reported as a side effect.²³ Nigella sativa was used on healthy adolescents (n = 48) to examine the efficacy of NS on anxiety, mood, and cognition in adolescents. Nigella sativa administered at 500 mg/day once daily for 4 weeks was effective in stabilizing mood, modulating anxiety positively, and decreasing anxiety.²⁵ This is because NS increases the level of hydroxytryptamine-5 and thus decreases anxiety. Also, NS and thymoquinone decrease NO, decrease brain gamma-aminobutyric acid, and provide an anxiolytic effect.³³

Regarding the safety of using NS in pediatrics, none of the included studies report a serious adverse event from using NS in pediatrics. Our analysis shows that the reported side effects in the included studies were not statistically significant. However, a few mild adverse events have been reported. Two patients experienced an exacerbation of seizures, which might raise concern when using NSO with epileptic children, and 1 patient developed nausea and vomiting after black seed oil administration.¹⁴

The gastrointestinal problems reported by Shawki et al¹⁴ were similar to those of Kalus et al,¹⁰ who reported a mild gastrointestinal problem after black seed oil administration on an empty stomach. In another study, 1 patient reported constipation with the use of black seed extract.²⁷ Momen et al¹³ did not report an adverse event from using a mixture of NS and Thymus vulgaris extracts, and none of the children discontinued the treatment. A topical form of NS was used for acne, skin infections, and allergic rhinitis. None of the studies that used the topical form of NS reported any serious side effects. Some nasal dryness was reported in 1 study when NSO was used as nasal drops.²⁵ The meta-analysis in our study shows that the occurrence of side effects was not statistically significant. Nigella sativa seeds are approved by the United States Food and Drug Administration and recognized to be safe as a flavoring agent or an adjuvant in food (21 CFR§182.20).⁴⁵ An overview of NS safety concluded that studies assessing the toxicity of NS have reported it as a safe medicinal plant.⁹ The extract of NS seeds, and its bioactive components, are considered chemicals with low toxicity^9,10,29 and a wide safety margin.^46,47 For thymoquinone and NS extracts, a high-quality clinical trial investigating the relationship of NS dose, form, and duration of use to clinical outcomes is needed.

Information about the bioavailability of NS constituents after human consumption is lacking, and additional information about the absorption, distribution, and disposition of NS bioactive constituents in humans is needed.³

For future studies, more detailed and high-quality studies are required to establish the safety and efficacy of using NS in the pediatric population. None of the studies included in this review measures the participants’ adherence to the intervention. Frequent supervision and follow-ups on compliance and adherence to the intervention are required in those studies conducted on pediatrics.