Nigella Sativa in COVID
Black seed or N. sativa that belongs to the Ranunculacea family has a rich historical and religious background. It is native to southwest Asia but it has been cultivated and used in different parts of the world as a spice, food additive, as well as herbal medicine for a wide range of illnesses. (8)
Traditionally, it has been used in different forms to treat many diseases including asthma, chronic renal failure, hypertension, diabetes, inflammation, cough, bronchitis, headache, eczema, fever, dizziness and influenza. Experimentally, it has been demonstrated that N. sativa extracts and the main constituent of their volatile oil, thymoquinone, possess antioxidant, anti-inflammatory and hepatoprotective properties.
Nigella Sativa increasingly is being looked as at a very useful adjunct in the treatment of Covid cognitive impairment, early reduction in acute Covid symptoms, and probably reduction in risk itself of Covid by blocking spike protein.
Most research into Nigella as described below was performed using its active ingredient Thymoquinone (TQ) so dosages cannot be accurately translated into Nigella dosages. When Nigella was used it was usually in doses of 500mg twice daily, although non-mainstream research eg FLCCC (24) recommend 40mg/kg per day. Preliminary studies at our clinic using 500mg twice daily provided a roughly 30% improvement in symptoms. These results are below what was expected, and we are currently looking at 30mg/kg/day, and ideally using formulations with concentrated TQ.
Webmd provides basic dosing in adults of 1 to 2.5 gm/day. Shahdaat et al (23) used 500mg of nigella twice daily for 9 weeks demonstrating in healthy subjects enhancement in memory, attention and cognition. Nigella has reportedly been used at doses up to 5 gm daily, but references available.
Koshak et al (16) used 500mg twice daily in a trial with new COVID outpatients showing a 46% recovery within 14 days, significantly less than in non-treated group. A small number of patients (3.4%) could not tolerate the nigella.
Dosing- Nanoformulation and potential Interactions
By encapsulating TQ in nanoformulations to enhance its pharmacological properties, with excellent physiochemical properties useful for the continuing research. This product is not available to us at the present time, and I expect will eventually become available as a Pharma product.
For long-term oral consumption, TQ at a dose of 10 mg/kg is safe in mice and does not exert any toxic effect. The results provide safety information of TQNLC, which would further help researchers in clinical use.(5)
Webmd (10) describes potential interactions:
• with diabetes medication as black seed may lower blood glucose levels
• with immunosuppressants. This may be important if on immunosuppressants eg following transplants
• with anti-coagulants owing to its own anti-clotting properties
• with blood pressure tablets again as it lowers blood pressure itself
• with CNS depressants/ sedatives. It cause sleepiness and slowed breathing
• with cyclosporine it should be avoided
• with diuretics which may drop potassium levels excessively
• with Serotonergics- potential for Serotonin Syndrome
Nigella Sativa in Covid
N sativa, due to its wide range of bioactive components such as TQ and nigellimine, appears to offer a range of benefits for treating COVID-19, such as blocking the introduction of the virus to pneumocytes; providing ionophores to improve zinc intake, thereby improving the host immune response to SARS-CoV-2; and preventing the virus from replicating.(11)
Badary et al (11) described how TQ could potentially inhibit COVID-19 by binding to the receptor-binding domain on the spike protein of SARS-CoV-2, thus hindering hinder virus entry into the host cell. Additionally, they felt it may bind to the SARS-CoV-2 envelope protein and inhibit its ion channel and pore formation activity as well as other studies showing that TQ might display inhibitory action against the SARS CoV2 protease, which would halt viral replication.(11)
They also demonstrated that TQ has a good affinity against ACE2 receptors, which allows it to interfere with virus uptake into the host cell, similar to what has been shown with the blood pressure tablet Telmisartan.(11)
Bencheqroun,H et al.(13) used Thymoquinone in outpatient treatment of SARS-CoV infections and demonstrated a significantly faster reduction in symptom burden, improved immune response and inhibition of the entry of 5 SARS‐CoV‐2 variants. They found thymoquinone to be well tolerated and predictably safe.
Their analysis of T lymphocytes showed a significant increase in cytotoxic CD8+ T lymphocytes and helper CD4+ T lymphocytes with native/central memory phenotype (CD45RA+CCR7+), from baseline to day 14. This suggested that TQF supports the recovery of the immune system against SARS-CoV-2, which likely helps prevent the progression to severe SARS-CoV-2. Notably, their molecular docking models and in vitro experiments confirmed TQF anti-SARS-CoV-2 inhibitory effects against five SARS-CoV-2 variants, including Omicron, likely through viral entry antagonism at the ACE-2 receptor level, combined with the in vivo immunomodulatory activity and the potential anti-inflammatory actions of TQF may in aggregate explain the positive signals noted in this clinical trial.
Other Nigella (and Thymoquinone) benefits
Thymoquinone (TQ) is the main bioactive principle in N Sativa, and this has been found to confer a range of therapeutic advantages including antioxidant, anti-inflammatory, anticancer, antibacterial, antifungal, anticoagulant, anti-sepsis, and anticonvulsant activity.(11)
N Sativa seeds have also demonstrated immunomodulatory effects, while several studies suggest that N Sativa seeds have some antiviral effects. In addition to its immunomodulatory and antioxidant properties, however, N Sativa and its active constituents have also been noted to provide anti-ischaemic effects in several organs, including the brain, kidney, heart, liver, and intestines. Such evidence strongly suggests that N. sativa seeds and their active constituents may have significant therapeutic potential against COVID-19 and its complications.(11)
Nigella sativa itself is a complex mix of natural chemicals, consisting of over 100 ingredients. It is a rich source of proteins, essential fatty acids, carbohydrates, minerals and vitamins. The active components of black seed are Thymoquinone (TQ), dithymoquinone, thymol, thymohydroquinone, nigellone, and fixed oils. of which the most studied, and with the major benefits is Thymoquinone, which at present is not available commercially. (1)
It has been more than 50 years since thymoquinone (TQ), a promising biologically active phytochemical, was first isolated and identified from the Nigella sativa seeds. Very recently the advancement in nanotechnology has led to develop and test novel nanoparticle formulations for thymoquinone against disease models with the intention to move this molecule into the clinical trials and eventually to the clinical practice, particularly into breast cancer treatment.(1)
Figure 1: Potential Beneficial Effects of Thymoquinone in COVID-19
Source: Osama A Badary, Marwa S Hamza, and Rajiv Tikamdas. Thymoquinone: A Promising Natural Compound with Potential Benefits for COVID-19 Prevention and Cure. Drug Des Devel Ther 2021. doi: 10.2147/DDDT.S308863
Aquib et al (14) used TQ in combination with the antidepressant fluoxetine demonstrating anti-depressant and anti-oxidant effects and signals possible future adjunctive treatment in depression.
Hannan et al (15) showed nigella sativa and TQ to be effective in treating various kidney diseases and can protect against kidney injury caused by various xenobiotics, namely chemotherapeutic agents, heavy metals, pesticides, and other environmental chemicals. Black cumin can also protect the kidneys from ischaemic shock. The mechanisms underlying the kidney protective potential of black cumin and TQ include antioxidation, anti-inflammation, anti-apoptosis, and antifibrosis which are manifested in their regulatory role in the antioxidant defence system, NF-κB signalling, caspase pathways, and TGF-β signalling.(15)
Alam et al (28) demonstrated improvements in renal failure with significant reduction in blood urea, serum creatinine, and 24-h total urine protein and a significant improvement in 24-h total urine volume and glomerular filtration rate. N. sativa oil supplementation along with alpha-keto analogue is more more efficacious and safe in delaying the progression of disease patients with CKD Stages 3 and 4. CKD symptoms of “anorexia, nausea, vomiting, weakness, weight loss, fever, pruritus, headache, dyspnoea, hypertension, swelling over the body, oliguria, burning during micturition, and anaemia.”
Various studies have demonstrated the protective effect of Nigella Sativa and Thymoquinone against lung damage and fibrosis.(26) There are a small number of papers recommending it’s use in Covid -related lung disease. Khazdair et al (27) described N. sativa and TQ as reducing the level of pro-inflammatory mediators including, IL-2, IL-4, IL-6, and IL-12, while enhancing IFN-γ. Nigella sativa and TQ increased the serum levels of IgG1 and IgG2a, and improved pulmonary function tests in restrictive respiratory disorders.(27)
Elevated D-Dimer -a persisting problem in Long Covid
A recurring problem in management is in patients with persistently elevated D-Dimer results which give us indications of micro-clotting, a process that is being researched in a number of areas, eg in the cause of cardiovascular disease in MINOCA and in the ME/CFS patients being researched at Griffith University. Griffith has published research to show the benefit of Low Dose Naltrexone with its effect on Natural Killer Cell function, Glymphatic system function and TRP pathways. But it is also seen to affect the TLR4 pathway, although in a different manner than Nigella Sativa. Our current trials are looking at both these products, separately and in combination, as well as Omega 3, in the management of the D Dimer elevations.
COVID-19 studies have shown that infected patients typically develop thrombocytopenia with higher D-dimer levels, while the rates of developing thrombocytopenia in patients with severe COVID-19 are even higher. Viral infections often cause systemic inflammatory responses and interfere with the balance of procoagulants and anticoagulants, and in severe or critically ill patients, large quantities of inflammatory mediators, hormones and immunoglobulin are released, leading to blood hypercoagulability. The level of interleukins, especially IL-6, IL-7, IL-2, TNFα and others has been similarly found to be increased in patients with COVID-19.(11)
Research by Muralidharan-Chari et al (12) found that Thymoquinone has direct effects on suppressing the downstream effects of TNF-α. Thymoquinone has only a minimal and a modulatory effect on the coagulation of normal blood and plasma and with no effect at higher concentration on blood coagulation, suggesting that it is a suitable candidate and has the potential to be utilized both as an alternative to preventative anticoagulants and as a supplement to the existing therapies for infections, chemotherapies, and anticoagulant therapies.(12)
Nigella Sativa in Parkinsons and Alzheimers Diseases and Potential for Long Covid Cognitive Impairment
The overall studies into Covid and Long Covid have shown a concerning increase in neurodegenerative disease, especially Parkinsons and Alzheimer’s Diseases. The continuing cognitive impairment in Long Covid can also very difficult to treat. The DNA mutations we have found are described in : https://www.mcmc-research.com/post/long-covid-part-2-dna-mutations-that-underpin-pots-and-long-covid-1
Nigella provides a useful adjunct to the protocols in place. It’s usefulness in Parkinson’s Disease (PD) and Alzheimers Disease (AD) is described in these studies below. Perhaps more importantly it shows clues to the metabolic processes that underpin the Long Covid cognitive impairment.
Uddin et al (17) demonstrated that TQ protected against neurotoxins via amelioration of neuroinflammation, oxidative stress, and apoptosis, thereby protecting neurodegeneration in Parkinson’s diseases research. Dong et al (18) findings suggested that TQ alleviates progressive dopaminergic neuropathology by activating the Nrf2/ARE signalling cascade and by attenuating oxidative stress, thus demonstrating that TQ is a potential novel drug candidate for the treatment of PD.
Ardah et al (19) found that in mouse studies that TQ treatment restored antioxidant enzymes, prevented glutathione depletion, inhibited lipid peroxidation, and attenuated pro-inflammatory cytokines . TQ also decreased the raised levels of inflammatory mediators, such as COX-2 and iNOS. Therefore, TQ was thought to protect against PD and the observed neuroprotective effects are attributed to its potent antioxidant and anti-inflammatory properties. Moreover, the in vitro analysis found that TQ significantly inhibited α-synuclein aggregation and prevented cell death induced by pre-formed fibrils. Thus, TQ not only scavenges the MPTP-induced toxicity but also prevents α-synuclein-fibril formation and its associated toxicity.(19)
Alzheimer’s disease (AD) is characterized by a robust inflammatory response elicited by the accumulation and deposition of amyloid-β (Aβ) within the brain. Aβ induces detrimental inflammatory responses through toll-like receptors (TLRs) signaling pathway.(22) Abulfadi et al (22) in their rat studies administered TQ orally at doses of 10, 20, and 40 mg/kg/day for 14 days after artificially inducing Alzheimers Disease in their animals. TQ improved AD rat cognitive decline, decreased Aβ formation and accumulation, significantly decreased TNF-α and IL-1β at all levels of doses and significantly downregulated the expression of TLRs pathway components as well as their downstream effectors NF-κB and IRF-3 mRNAs at all levels of doses.
They found that high dose TQ (40 mg/kg) showed significant increase in TLR-2 and TLR-4 signalling pathways compared to the control group. They concluded that TQ improved the AD-induced cognitive decline and brain morphological changes through its anti-inflammatory effect. The anti-inflammatory effect exerted by TQ may depend not only on the inhibition of TLR-2/TLR-4 signalling pathways to produce its toxicity through releasing of pro-inflammatory cytokines, but also on the mRNA expression of TLR-2/TLR-4. Both TLR-2 and TLR-4 are targets for TQ; TQ also inhibits MyD88-dependent and TRIF-dependent pathways. The dual anti- and pro-inflammatory effects of TQ require further investigation, specifically the protein level of TLR-2, TLR-4, MyD88, TRIF, IRF-3, and NF-κB.(22)
In Alzheimers disease research, Elibol et al (20) found that TQ has the capacity to recover the neuropathology by removing Aβ plaques and by restoring neuron viability. Poorgholam et al (21) Amyloid beta caused cognitive dysfunction reflected by increasing initial and step-through latency along with plaque formation and degeneration of pyramidal cells in the hippocampus. Thymoquinone (TQ) administration ameliorated this effect by significant reductions in plaque formation in CA1 region of the hippocampus and increased latency time. It also increased the number of surviving neurons in the hippocampus.
Nigella sativa in modulating critical TLR4 responses
There is increasing evidence from the DNA studies by Dr Valerio Vittone that it mutations in the “first responders,” in particular TLR4 that determine the altered immune response that occurs in patients with severe reactions and Long Covid. One DNA mutation alone cannot cause the level of damage that occurs with infections. These are discussed in https://www.mcmc-research.com/post/long-covid-part-2-dna-mutations-that-underpin-pots-and-long-covid-1
Toll-like receptor 4 (TLR4) is a crucial receptor in neuroinflammation and apoptotic neuronal death, and increasing evidences indicated that β2-microglobulin (B2M) is thought to be a major contributor to age-related cognitive decline, and abnormalities of B2M are commonly seen in Long Covid.
Research by Zhong et al (9) results support the TLR4 contributes to B2M-induced age-related cognitive decline due to neuroinflammation and apoptosis through TLR4/MyD88/NF-κB signalling pathway via a modulation of hippocampal neurogenesis and synaptic function. This may provide an important neuroprotective mechanism for improving age-related cognitive decline, and likely part of the complex cause of the cognitive impairment seen in Long Covid.
Zhong et al showed that in the absence of TLR4, B2M treatment improved hippocampus neurogenesis and increased synaptic related proteins and that deletion of TLR4 could significantly increase synaptic related protein, decrease neuroinflammatory factors, inhibit apoptotic neuronal death, and regulate MyD88/NF-κB signal pathway after B2M treatment, thus may provide an important neuroprotective mechanism for improving age-related as well as Covid-related cognitive decline.
Figure 2: Biological Activities of Thymoquinone
Source: Sikkander,A, Yasmeen, K. Review on Defensive Roles of Thymoquinone Nanobiosensoring Prospective in Opposition to Cancer. 2021. ResearchGate. 10.46243/jst.2021.v6.i2.pp58-63
Expression of many pro-inflammatory cytokines is controlled by the NF-kappaB signaling pathway. NF-kappaB is induced by LPS through activation of TLR4. Melanins extracted from fungal, plant and human sources modulate cytokine production and activate NF-kappaB pathway. Oberg et al (6) showed that a herbal melanin (HM) from Nigella sativa L. modulates cytokine production and suggested it as a ligand for TLR4. HM can modulate the inflammatory response by inducing IL-8 and IL-6 production via TLR4-dependent activation of the NF-kappaB signaling pathway.(6)
Nano-TQ effectively augments other treatments in breast and cervical cancer cells (3)(4). But Thymoquinone does appear to be far more than that. TQ reduces the expression of TLR2 and TLR4, reducing levels of the inflammatory cytokines TNF, IL-1 and NFB, and reduces CRP Rheumatoid factor and various haematological markers.(7) Arjumand et al (7) found TQ possesses significant anti-arthritic activity which can be due to its anti-inflammatory and immunomodulatory effects.
Nigella Sativa is one of the world’s longest-used herbal medicines, with a broad range of applications, and with its inherent safety provides a very useful adjunctive treatment in management of Covid-related disease. It’s active ingredient Thymoquinone appears to have a wide array of positive effects for malignancy and neurodegenerative diseases.
1. Abu Khader, M, Khan, S. Thymoquinone and Nanoparticles: A Promising Approach for the Clinical Trials. 2017. Journal of Bionanoscience DOI: 10.1166/jbns.2017.1447
2. Sikkander,A, Yasmeen, K. Review on Defensive Roles of Thymoquinone Nanobiosensoring Prospective in Opposition to Cancer. 2021. ResearchGate. 10.46243/jst.2021.v6.i2.pp58-63
3. El-Far,A, Al Jaouni,S, Li, W, Mousa,S. Protective Roles of Thymoquinone Nanoformulations: Potential Nanonutraceuticals in Human Diseases. 2018, Nutrients.https://doi.org/10.3390/nu10101369
4. Ng,W et al. Thymoquinone-Loaded Nanostructured Lipid Carrier Exhibited Cytotoxicity towards Breast Cancer Cell Lines (MDA-MB-231 and MCF-7) and Cervical Cancer Cell Lines (HeLa and SiHa). Biomed Research International. 2014. https://doi.org/10.1155/2015/263131
5. Ong YS, Saiful Yazan L, Ng WK, Noordin MM, Sapuan S, Foo JB, Tor YS. Acute and subacute toxicity profiles of thymoquinone-loaded nanostructured lipid carrier in BALB/c mice. Int J Nanomedicine. 2016;11:5905-5915
6. Oberg F, Haseeb A, Ahnfelt M, Pontén F, Westermark B, El-Obeid A. Herbal melanin activates TLR4/NF-kappaB signaling pathway. Phytomedicine. 2009 May;16(5):477-84. doi: 10.1016/j.phymed.2008.10.008. Epub 2008 Dec 21. PMID: 19103478.
7. Arjumand,S et al. Thymoquinone attenuates rheumatoid arthritis by downregulating TLR2, TLR4, TNF-α, IL-1, and NFκB expression levels. 2019. Biomedicine and Pharmacotherapy. https://doi.org/10.1016/j.biopha.2019.01.006
8. Gholamnezhad, Z., Boskabady, M.H. & Hosseini, M. Effect of Nigella sativa on immune response in treadmill exercised rat. BMC Complement Altern Med 14, 437 (2014). https://doi.org/10.1186/1472-6882-14-437
9. Zhong, Q., Zou, Y., Liu, H. et al. Toll-like receptor 4 deficiency ameliorates β2-microglobulin induced age-related cognition decline due to neuroinflammation in mice. Mol Brain 13, 20 (2020). https://doi.org/10.1186/s13041-020-0559-8
11. Osama A Badary, Marwa S Hamza, and Rajiv Tikamdas. Thymoquinone: A Promising Natural Compound with Potential Benefits for COVID-19 Prevention and Cure. Drug Des Devel Ther 2021. doi: 10.2147/DDDT.S308863
12. Muralidharan-Chari V, Kim J, Abuawad A, Naeem M, Cui H, Mousa SA. Thymoquinone Modulates Blood Coagulation in Vitro via Its Effects on Inflammatory and Coagulation Pathways. Int J Mol Sci. 2016;17(4):474. Published 2016 Mar 30. doi:10.3390/ijms17040474
13. Bencheqroun,H et al. A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of ThymoQuinone Formula (TQF) for Treating Outpatient SARS-CoV-2. 2022. MDPI. https://doi.org/10.3390/pathogens11050551
14. M. Aquib et al., Antidepressant Effect of Thymoquinone in Animal Models of Depression. Drug Research, 2014. : 10.1055/s-0034-1389920
15. Hannan MA, Zahan MS, Sarker PP, Moni A, Ha H, Uddin MJ. Protective Effects of Black Cumin (Nigella sativa) and Its Bioactive Constituent, Thymoquinone against Kidney Injury: An Aspect on Pharmacological Insights. Int J Mol Sci. 2021 Aug 23;22(16):9078. doi: 10.3390/ijms22169078. PMID: 34445781; PMCID: PMC8396533.
16. Koshak AE, Koshak EA, Mobeireek AF, et al. Nigella sativa for the treatment of COVID-19: An open-label randomized controlled clinical trial. Complement Ther Med. 2021;61:102769. doi:10.1016/j.ctim.2021.102769
17. Uddin MN, Hoq MI, Jahan I, Siddiqui SA, Clinton CD, Ibrahim M, Islam MS, Jakaria M. The Mechanistic Role of Thymoquinone in Parkinson's Disease: Focus on Neuroprotection in Pre-Clinical Studies. Curr Mol Pharmacol. 2021;14(6):1083-1092. doi: 10.2174/1874467214666210105140944. PMID: 33402092.
18. Dong J, Zhang X, Wang S, Xu C, Gao M, Liu S, Li X, Cheng N, Han Y, Wang X, Han Y. Thymoquinone Prevents Dopaminergic Neurodegeneration by Attenuating Oxidative Stress Via the Nrf2/ARE Pathway. Front Pharmacol. 2021 Jan 14;11:615598. doi: 10.3389/fphar.2020.615598. PMID: 33519481; PMCID: PMC7840486.
19. Ardah MT, Merghani MM, Haque ME. Thymoquinone prevents neurodegeneration against MPTP in vivo and modulates α-synuclein aggregation in vitro. Neurochem Int. 2019 Sep;128:115-126. doi: 10.1016/j.neuint.2019.04.014. Epub 2019 Apr 24. PMID: 31028778.
20. Birsen Elibol, Merve Beker, Sule Terzioglu-Usak, Tugce Dalli, Ulkan Kilic, Thymoquinone administration ameliorates Alzheimer's disease-like phenotype by promoting cell survival in the hippocampus of amyloid beta1–42 infused rat model, Phytomedicine, 2020. https://doi.org/10.1016/j.phymed.2020.153324.
21. Poorgholam P, Yaghmaei P, Hajebrahimi Z. Thymoquinone recovers learning function in a rat model of Alzheimer's disease. Avicenna J Phytomed. 2018;8(3):188-197.
22. Abulfadl Y, El-Maraghy N, Ahmed AE, Nofal S, Abdel-Mottaleb Y, Badary O. Thymoquinone alleviates the experimentally induced Alzheimer’s disease inflammation by modulation of TLRs signaling. Human & Experimental Toxicology. 2018;37(10):1092-1104. doi:10.1177/0960327118755256
23. Muhammad Shahdaat Bin Sayeed, Md. Asaduzzaman, Helal Morshed, Md. Monir Hossain, Mohammad Fahim Kadir, Md. Rezowanur Rahman, The effect of Nigella sativa Linn. seed on memory, attention and cognition in healthy human volunteers, Journal of Ethnopharmacology, 2013 https://doi.org/10.1016/j.jep.2013.05.004.
25. Nordin, A., Kamal, H., Yazid, M.D. et al. Effect of Nigella sativa and its bioactive compound on type 2 epithelial to mesenchymal transition: a systematic review. BMC Complement Altern Med 19, 290 (2019). https://doi.org/10.1186/s12906-019-2706-2
26. Noorbakhsh MF, Shaterzadeh-Yazdi H, Hayati F, Samarghandian S, Farkhondeh T. Protective Effects of Thymoquinon on Pulmonary Disorders in Experimental Studies. Tanaffos. 2018;17(4):211-222.
27. Khazdair MR, Ghafari S, Sadeghi M. Possible therapeutic effects of Nigella sativa and its thymoquinone on COVID-19. Pharm Biol. 2021;59(1):696-703. doi:10.1080/13880209.2021.1931353
28. Alam, Mohd. Ashraf1; Nasiruddin, Mohammad1,; Haque, Shahzad F.2; Khan, Rahat Ali1. Evaluation of Safety and Efficacy Profile of Nigella sativa Oil as an Add-On Therapy, in Addition to Alpha-Keto Analogue of Essential Amino Acids in Patients with Chronic Kidney Disease. Saudi Journal of Kidney Diseases and Transplantation 31(1):p 21-31, Jan–Feb 2020. | DOI: 10.4103/1319-2442.279943