Introduction
Nigella sativa L. (N. sativa), also known as black cumin or black seeds, is an annual flowering plant of the Ranunculaceae family. It is characterized by its delicate pale blue and white flowers and small, angular black seeds. The seeds of N. sativa are the most commonly used part of the plant and are known for their strong aromatic fragrance. 1, 2, 3, 4 The chemical profile of N. sativa seeds is quite complex. It has been widely used in traditional medical systems such as Unani, Ayurveda, and Siddha. They contain various bioactive compounds such as thymoquinone, nigellidine, nigellimine, dithymoquinone, thymohydroquinone, and thymol. The main active component responsible for its pharmacological properties is thymoquinone, found in the essential oil. The plant has a low degree of toxicity and has been used in food, pharmaceutical, and cosmetic industries.5, 6
These seeds have a significant historical and cultural significance, with documented use in various civilizations throughout history. They have been used as a traditional remedy for various ailments and as a culinary spice in many cultures:
Ancient Egypt: N. sativa seeds were found in the tomb of King Tutankhamun, emphasizing their historical use in ancient Egypt. They were used for culinary purposes and were also recognized for their medicinal properties.
Traditional Ayurveda: In traditional Indian medicine, known as Ayurveda, N. sativa seeds were used to treat various ailments, including digestive issues, respiratory conditions, and skin disorders.
Traditional Chinese Medicine: These seeds have a history of use in traditional Chinese medicine, where they were employed for their anti-inflammatory, diuretic, and digestive properties.
Greco-Roman Civilization: N. sativa seeds were also recognized in Greco-Roman civilization for their medicinal properties, with references in the works of Dioscorides, a renowned Greek physician and botanist.
Islamic Medicine: N. sativa seeds have been extensively used in traditional Islamic medicine for various therapeutic purposes. They are mentioned in the Hadith (sayings of Prophet Muhammad) as a remedy for a range of ailments.
Contemporary Research: In recent years, there has been a growing interest in the scientific community to study the potential health benefits of N. sativa seeds. Research has focused on their antioxidant, anti-inflammatory, and antimicrobial properties, as well as their potential role in the management of various chronic diseases.7, 8, 9
Plant Profile of N. sativa
Botanical Name: N. sativa Linn.
Family: Ranunculaceae
Vernacular names
English: Black cumin
Hindi: Kalonji
Arabic: Habat Al-Barakah
Sankrit: Krishana Jiraka 10
Distribution
N. sativa is cultivated in various countries in the world such as India, Pakistan, Saudi Arabia, South Europe, Turkey, Syria and Middle Eastern Mediterranean region whereas it is native to North Africa, Southern Europe and Southwest Asia.11
Phytochemical Composition of N sativa
The main active chemical constituents are thymoquinone (25-50%), dithymoquinone, thymohydroquinone, p-cymene (5-15%), carvacrol (6-10%), 4-terpineol (2-6%), sesquiterpene, longifolene (1-7%), tanethol (1-5%), α-pinene and thymol etc. N. sativa seeds contain two types of alkaloids; i.e. isoquinoline alkaloids e.g. nigellicimine-N-oxide, nigellicimine and pyrazol alkaloids or indazole ring containing alkaloids which include nigellicine and nigellidine. Furthermore, N. sativa seeds have alpha-hederin, a saponin and water soluble pentacyclic triterpene, a potent anticancer agent.12 The pharmacological actions of N. sativa are mainly due to quinine constituents in which thymoquinone is the most active constituents. The seeds of N. sativa consist of fat (28.5%), protein (26.7%), carbohydrates (24.9%), crude fibre (8.4%) and total ash (4.8 %), vitamins, minerals (Fe, Cu, Zn and P etc) and unsaturated fatty acids, mainly linoleic acid, oleic acid, dihomolinoleic acid, eicodadienoic acid, saturated fatty acids such as palmitic and stearic acid. α- sitosterol is also contained as major sterol (6.57-20.92% of total sterols).13 Other reported chemical constituents are nigellone, avenasterol-7-ene, avenasterol-5-ene, stigmastanol, stigmasterol-7-ene, campesterol, citrostadienol, obtusifoliol, lophenol, β-amyrin, butyro-spermol, cycloartenol, 24-methylene-cycloartanol, taraxerol, tirucallol, cholesterol, volatile oil (0.5-1.6%), fatty oil (35.6-41.6%), oleic acid, esters of unsaturated fatty acids, esters of dehydrostearic and linoleic acid, melanthin, melanthigenin, aliphatic alcohol, tannin, resin, reducing sugar and glycosidal saponin. 1, 2, 3, 14 Analytical techniques, such as high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS), have been extensively employed for the identification and quantification of these bioactive constituents.
Extraction and Formulation Techniques of N. sativa
Extraction techniques
Traditional Extraction Methods: The traditional methods for N. sativa extraction involve processes such as maceration, percolation, and distillation. These methods have been used for centuries and are known for their simplicity and cost-effectiveness. However, they often yield lower extraction efficiencies and may lead to the degradation of certain bioactive compounds.
Modern Extraction Approaches: Modern extraction techniques of N. sativa (Figure 1, Figure 2), including solvent extraction, supercritical fluid extraction, and microwave-assisted extraction, have gained prominence for their ability to improve extraction yields and preserve the integrity of bioactive compounds. Supercritical fluid extraction, in particular, has shown promise in maximizing the extraction of volatile compounds while minimizing the use of organic solvents. 15
It is noteworthy to mention that the oil yield of N. sativa has superior quality and safety compared with many vegetable and seed oils which require further refining, bleaching, and deodorizing (RBD) 16 which may result in hazardous thermal processing contaminants such as 3-MCPD. 17
Formulation Strategies
Encapsulation Techniques: Encapsulation techniques, such as nanoemulsion, microencapsulation, and solid lipid nanoparticles, have been employed to enhance the stability and bioavailability of N. sativa extracts. These approaches protect the bioactive components from degradation and improve their targeted delivery, thereby maximizing their therapeutic efficacy. 18
Combination Formulations: Formulating N. sativa extracts with other natural compounds or pharmaceutical agents has been explored to amplify their therapeutic effects. Synergistic combinations have been studied for their potential in addressing various health conditions, including inflammation, oxidative stress, and microbial infections. 19
Pharmacological Properties of N sativa
Research (Table 1) has shown that N. sativa exhibits potential in the treatment of various types of cancers.20, 21, 22, 23 cardiovascular system disorders,24 gastrointestinal diseases. 25, 26 liver diseases. 27 asthma. 28 depression. 29, 30, 31 headache, migraine. 32 analgesic, 15 rheumatoid arthritis, 24 infertility, 33 wound healing. 34 neurological 35 and nephrological disorders. 36 Studies have also demonstrated its antimicrobial, 37 antifungal, 38 immunomodulatory, anti-inflammatory 39 and antioxidant properties, 40, 41 N. sativa has also shown potential as a natural remedy for COVID-19, with studies reporting its positive effects on immune function and viral clearance. 42, 43, 44
Additionally, N. sativa has been investigated for its potential in managing diabetes, with studies demonstrating its hypoglycemic activity and improvement in blood glucose levels. 45-46] Furthermore, N. sativa has been reported to have antiviral efficacy against various viruses, and could be used as an adjuvant therapy in the management of monkeypox infection. 46, 47 Overall, N. sativa shows promise in various therapeutic applications and further research is needed to explore its mechanisms of action and clinical use.
Clinical Studies and Efficacy of N sativa
Anti-inflammatory and Immunomodulatory Effects: Several studies have highlighted the anti-inflammatory and immunomodulatory properties of N. sativa. In a randomized, double-blind, placebo-controlled trial, it was found that supplementation with N. sativa significantly reduced markers of inflammation in patients with rheumatoid arthritis. Additionally, a systematic review by Butt et al. demonstrated the immunomodulatory effects of N. sativa, suggesting its potential use in immune-related disorders. 48, 49
Anticancer Potential: Research has suggested that N. sativa may exhibit anticancer properties through various mechanisms, including apoptosis induction, cell cycle arrest, and anti-proliferative effects. For instance, a study by Gali-Muhtasib et al. reported the potential of thymoquinone, a key component of N. sativa, in suppressing tumor growth and enhancing the efficacy of conventional cancer therapies.50
Cardioprotective Effects: Several clinical trials have explored the cardioprotective effects of N. sativa. For instance, a study by Dehkordi et al. emonstrated the beneficial effects of N. sativa supplementation in reducing cardiovascular risk factors, including blood pressure and lipid profiles, in patients with mild hypertension.51
Antimicrobial Activity: N. sativa has exhibited promising antimicrobial properties against various pathogens, including bacteria, viruses, and fungi. In a study by Ali and Blunden, the essential oil extracted from N. sativa seeds demonstrated significant antimicrobial activity against a range of pathogens, suggesting its potential application in combating infectious diseases.52
Table 1
Pharmacological activities of N. sativa and their respective mechanisms of action:
Quality Control and Standardization of N. sativa
Authentication Techniques for N. Sativa: Due to the rising concerns regarding adulteration and misidentification of herbal products, various authentication techniques have been developed to ensure the purity and authenticity of N. sativa. These include DNA barcoding, thin-layer chromatography (TLC) fingerprinting, and nuclear magnetic resonance (NMR) spectroscopy. These methods play a crucial role in verifying the identity and quality of N. sativa and its derived products. 15
Regulatory Guidelines and Standardization: The lack of standardized guidelines poses a significant challenge in maintaining the quality and consistency of N. sativa based products. International regulatory authorities, including the World Health Organization (WHO) and the United States Pharmacopeia (USP), have emphasized the necessity of establishing comprehensive quality control standards for herbal medicines. Harmonization of these guidelines could facilitate the development of uniform protocols for the quality assessment and standardization of N. Sativa.10, 11
Regulatory Status and Inclusion in Pharmacopeia of N. sativa
Regulatory Status of N. Sativa: The regulatory status of N. sativa varies across different regions and countries. While some countries have included it in their pharmacopeia as a traditional medicine, others have imposed restrictions on its use due to concerns regarding its safety and efficacy. The lack of standardized guidelines for the cultivation, processing, and quality control of N. sativa-based products has further complicated its regulatory status. In some regions, it is categorized as a dietary supplement, whereas in others, it falls under the domain of traditional herbal medicine 54, 55, 56
Inclusion in Pharmacopeia: The Egyptian Herbal Monograph Volume 3, published by the Egyptian Drug Authority (EDA) in 2022, marks a significant shift in the status of Black Seed, moving it beyond its traditional use as a medicinal plant to a prominent position in the pharmacopeia as a recognized pharmaceutical preparation. This transition signifies a notable evolution, as Black Seed is now treated as a drug available in pharmacies, thereby acknowledging its therapeutic potential and solidifying its place in mainstream healthcare practices.
Moreover, the inclusion of Black Seed in the pharmacopeia underscores the growing recognition of its efficacy and safety, backed by rigorous scientific scrutiny and standardization. The transformation of Black Seed into a pharmaceutical product reflects a shift towards evidence-based medicine and a departure from its previous status solely within the realm of traditional medicine. This paradigm shift emphasizes the need for standardized dosages, clear administration protocols, and adherence to pharmaceutical guidelines, ensuring consistent quality and efficacy of the Black Seed preparations available in pharmacies.
Furthermore, the integration of Black Seed into the pharmacopeia highlights the growing acceptance and endorsement of its medicinal properties by the mainstream healthcare community. This inclusion not only enhances accessibility for patients but also instills confidence among healthcare practitioners in prescribing Black Seed-based pharmaceuticals, thereby consolidating its position as a recognized and trusted therapeutic agent.
In summary, the repositioning of Black Seed from its historical usage in traditional medicine to its newfound status in the pharmacopeia as a pharmaceutical preparation available in pharmacies represents a significant advancement in the integration of traditional and modern healthcare systems. This transition not only underscores the transformative power of scientific validation but also serves as a testament to the growing acceptance of traditional herbal remedies within contemporary healthcare practices. 57
The inclusion of N. sativa in pharmacopeia has been a topic of debate among regulatory authorities and healthcare professionals. Some traditional medicine systems, such as the Unani and Ayurvedic systems, have long recognized the therapeutic value of N. sativa and have included it in their respective pharmacopeia. However, its inclusion in modern pharmacopeia remains limited, with ongoing discussions regarding its standardization, quality control, and clinical evidence. 54
Challenges and Opportunities
The standardization of N. sativa-based products poses significant challenges, including variability in active compound content, adulteration, and lack of robust clinical data. Developing standardized protocols for cultivation, extraction, and quality assessment is crucial to ensure the safety and efficacy of N. sativa-based formulations. Collaboration between regulatory authorities, research institutions, and herbal medicine practitioners is essential to establish comprehensive guidelines for the use of N. sativa in healthcare practices.
Safety and Side Effects Of N sativa
N. sativa has been used traditionally for its medicinal properties for centuries. Various studies have explored its potential health benefits, but it is essential to consider the safety aspects and potential side effects associated with its use.
Safety Profile
N. sativa is generally considered safe for consumption and has been used as a culinary and medicinal herb for its potential health benefits. According to a review published in the Asian Pacific Journal of Tropical Biomedicine, the safety profile of N. sativa is favorable, with a long history of use in traditional medicine without significant reported toxicity or adverse effects. 58
Adverse Reactions
Despite its generally favorable safety profile, some individuals may experience adverse reactions or side effects. Common reported side effects associated with the consumption of N. sativa include:
Allergic Reactions
In rare cases, allergic reactions, such as skin rashes, itching, and difficulty breathing, have been reported following the ingestion or topical application of N. sativa. Individuals with known allergies to plants in the Ranunculaceae family should exercise caution when using N. sativa.
Gastrointestinal Disturbances
Some individuals may experience mild gastrointestinal disturbances, such as nausea, vomiting, or an upset stomach, particularly when consuming N. sativa in higher doses or in concentrated forms. However, these effects are typically mild and transient.59
Drug Interactions
It is important to consider potential interactions between N. sativa and certain medications. N. sativa may interact with certain medications due to its potential to affect metabolic enzymes and drug transporters. Individuals taking medications should consult a healthcare professional before incorporating N. sativa into their regimen to avoid potential interactions and adverse effects.60
Future Directions and Challenges in Harnessing the Potential of N sativa
Future directions
Clinical Trials and Standardization: To fully unlock the potential of N. sativa, rigorous clinical trials are imperative. Establishing standardized protocols for dosage and administration is crucial in determining its efficacy and safety across diverse patient populations.
Mechanistic Understanding: Elucidating the precise molecular mechanisms underlying the therapeutic effects of N. sativa will provide insights into its mode of action and aid in the development of targeted therapies for specific ailments.
Formulation Development: Exploring innovative delivery systems and formulations, such as nanoparticles, liposomes, and nanoemulsions, can enhance the bioavailability and stability of bioactive compounds, thereby improving its therapeutic efficacy.
Drug Interactions and Safety Profile: Investigating potential drug interactions and evaluating the long-term safety profile of N. sativa is essential for its integration into mainstream medicine and ensuring patient well-being. 25, 26
Challenges
Quality Control and Standardization: The lack of standardized procedures for cultivation, harvesting, and extraction poses a significant challenge in ensuring consistent quality and potency of N. sativa-based products.
Bioavailability Issues: The poor bioavailability of certain bioactive compounds in N. sativa limits its therapeutic effectiveness, necessitating innovative strategies to enhance absorption and systemic delivery.
Regulatory Hurdles: Establishing regulatory frameworks and guidelines for the commercialization of N. sativa-based products is critical in ensuring their quality, safety, and efficacy for consumer use.
Global Awareness and Accessibility: Enhancing public awareness regarding the potential health benefits of N. sativa and ensuring its accessibility, especially in resource-constrained regions, remains a significant challenge for widespread adoption and utilization.
Conclusions
In conclusion, N. sativa represents a valuable natural resource with diverse pharmacological properties and immense therapeutic potential. Its botanical and chemical profile, traditional uses, pharmacological activities, extraction and formulation techniques, quality control measures, regulatory status, clinical efficacy, safety profile, and future research directions collectively contribute to its growing significance in modern medicine and nutraceutical industries. Its inclusion in pharmacopeias is limited, highlighting the need for comprehensive documentation of its botanical characteristics, chemical composition, and pharmacological properties to facilitate its integration into official monographs and guidelines. Comprehensive efforts are warranted to bridge the gap between traditional knowledge and contemporary scientific advancements, thereby facilitating the integration of N. sativa into evidence-based healthcare practices.
Author Contribution
“Conceptualization, A.U. and R.I.M.A.; methodology, A.U. and R.I.M.A.; data curation, A.U. and R.I.M.A.; writing—original draft preparation, A.U. and R.I.M.A.; writing—review and editing, A.U. and R.I.M.A.”
Article DOI
