Nigella Sativa for COVID-19: real-time analysis of all 23 studies

Nigella Sativa for COVID-19: real-time meta analysis of 10 studies

Covid Analysis (Preprint) (meta analysis)

• Statistically significant improvements are seen for mortality, hospitalization, recovery, cases, and viral clearance. 6 studies from 5 independent teams in 4 different countries show statistically significant improvements in isolation (3 for the most serious outcome).

• Meta analysis using the most serious outcome reported shows 51% [23‑69%] improvement. Results are better for Randomized Controlled Trials, similar after exclusions, and similar for peer-reviewed studies. Results are consistent with early treatment being more effective than late treatment.

• No treatment, vaccine, or intervention is 100% effective and available. All practical, effective, and safe means should be used based on risk/benefit analysis. Multiple treatments are typically used in combination, and other treatments may be more effective. Only 20% of nigella sativa studies show zero events with treatment. The quality of non-prescription supplements can vary widely [Crawford, Crighton].

• All data to reproduce this paper and sources are in the appendix.

Covid Analysis et al., 27 Sep 2022, preprint, 1 author.

Pharmacological Profile of Nigella sativa Seeds in Combating COVID-19 through In-Vitro and Molecular Docking Studies

Sherwani et al., Processes, doi:10.3390/pr10071346 (In Vitro)

In Vitro study of nigella sativa's effect on oxidative stress, hemolysis, proteolysis, and glycation, and In Silico study for SARS-CoV-2 antiviral potential, suggesting beneficial effects for COVID-19.

Sherwani et al., 11 Jul 2022, peer-reviewed, 8 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Efficacy of polyherbal formulations for prevention of COVID ‐19 infection in high‐risk subjects: A randomized open‐label controlled clinical trial

Chandra et al., Phytotherapy Research, doi:10.1002/ptr.7531

RCT 251 high-risk individuals in India, mostly with direct contact with COVID-19 positive patients, testing polyherbal formulations Infuza, which includes nigella sativa, and Kulzam. Both formulations showed lower risk, without statisical significance, while the best results were from the combination of both.

risk of case, 49.0% lower, RR 0.51, p = 0.36, treatment 4 of 52 (7.7%), control 8 of 53 (15.1%), NNT 14, Infuza.

risk of case, 87.0% lower, RR 0.13, p = 0.03, treatment 1 of 51 (2.0%), control 8 of 53 (15.1%), NNT 7.6, Infuza and Kulzam.

risk of case, 74.0% lower, RR 0.26, p = 0.09, treatment 2 of 51 (3.9%), control 8 of 53 (15.1%), NNT 9.0, Kulzam.

Chandra et al., 5 Jul 2022, Randomized Controlled Trial, India, peer-reviewed, 12 authors, study period 18 September, 2020 - 21 May, 2021, this trial uses multiple treatments in the treatment arm (combined with Infuza polyherbal formulation) - results of individual treatments may vary, trial CTRI/2020/08/027222.

Efficacy of a Persian herbal medicine compound on coronavirus disease 2019 (COVID-19): a randomized clinical trial

Setayesh et al., Integrative Medicine Research, doi:10.1016/j.imr.2022.100869

Small RCT 41 patients treated with nigella sativa, glycyrrhiza glabra, punica granatum, and rheum palmatum, and 41 control patients, showing shorter hospitalization with treatment.

risk of death, 7.9% higher, RR 1.08, p = 1.00, treatment 1 of 38 (2.6%), control 1 of 41 (2.4%).

oxygen time, 26.8% lower, relative time 0.73, p = 0.007, treatment mean 3.0 (±1.6) n=38, control mean 4.1 (±1.9) n=41.

hospitalization time, 28.7% lower, relative time 0.71, p < 0.001, treatment mean 5.7 (±1.9) n=38, control mean 8.0 (±1.8) n=41.

Setayesh et al., 3 Jun 2022, Randomized Controlled Trial, Iran, peer-reviewed, mean age 59.1, 7 authors, study period June 2020 - September 2020, this trial uses multiple treatments in the treatment arm (combined with glycyrrhiza glabra, punica granatum, and rheum palmatum) - results of individual treatments may vary, trial IRCT20200330046899N1.

A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of ThymoQuinone Formula (TQF) for Treating Outpatient SARS-CoV-2

Bencheqroun et al., Pathogens, doi:10.3390/pathogens11050551

52 patient RCT in the USA with nigella sativa component thymoquinone, showing improved recovery with treatment. There was a significantly faster decline in the total symptom burden, and a significant increase in CD8+ and helper CD4+ central memory T lymphocytes. The treatment group contained 5 more vaccinated patients and 7 more overweight patients. Authors also present in vitro results showing an inhibitory effect with five SARS-CoV-2 variants including omicron.

risk of hospitalization, 69.3% lower, RR 0.31, p = 0.44, treatment 0 of 29 (0.0%), control 1 of 23 (4.3%), NNT 23, relative risk is not 0 because of continuity correction due to zero events.

time to sustained clinical response, 9.1% lower, HR 0.91, p = 0.78, treatment 28, control 23, inverted to make RR<1 favor treatment, Kaplan–Meier.

time to sustained clinical response, 35.5% lower, HR 0.65, p = 0.25, treatment 28, control 23, inverted to make RR<1 favor treatment, Kaplan–Meier, high-risk patients.

risk of no viral clearance, 43.5% lower, RR 0.57, p = 0.31, treatment 5 of 21 (23.8%), control 8 of 19 (42.1%), NNT 5.5, day 14.

Bencheqroun et al., 7 May 2022, Double Blind Randomized Controlled Trial, placebo-controlled, USA, peer-reviewed, mean age 45.0, 25 authors, study period 27 May, 2021 - 27 September, 2021.

A phase I clinical trial to evaluate the safety of thymoquinone -rich black cumin oil (BlaQmax®) on healthy subjects: Randomized, double-blinded, placebo-controlled prospective study

Thomas et al., Toxicology Reports, doi:10.1016/j.toxrep.2022.04.020 (Dosing)

Phase 1 trial of high thymoquinone content (5%) black cumin oil finding treatment to be safe without any major side effects or adverse events.

There was a significant reduction in total cholesterol, LDL, and triglycerides, and increased HDL.

Thomas et al., 20 Apr 2022, Double Blind Randomized Controlled Trial, placebo-controlled, peer-reviewed, 6 authors.

Immune-boosting effect of natural remedies and supplements on progress of, and recovery from COVID-19 infection

Shehab et al., Tropical Journal of Pharmaceutical Research, doi:10.4314/tjpr.v21i2.13

Retrospective survey-based analysis of 349 COVID-19 patients, showing no significant difference with nigella sativa prophylaxis in unadjusted analysis. REC/UG/2020/03.

risk of severe case, 0.2% lower, RR 1.00, p = 1.00, treatment 4 of 39 (10.3%), control 22 of 214 (10.3%), NNT 4173, unadjusted, severe vs. mild cases.

Excluded in after exclusion results of meta analysis: unadjusted results with no group details.

Shehab et al., 28 Feb 2022, retrospective, multiple countries, peer-reviewed, survey, 7 authors, study period September 2020 - March 2021.

Inhibitory effect of thymoquinone from Nigella sativa against SARS-CoV-2 main protease. An in-silico study

Khan et al., Brazilian Journal of Biology, doi:10.1590/1519-6984.25066

In Silico analysis of thymoquinone from nigella sativa showing good binding affinity with SARS-CoV-2 M^pro.

Khan et al., 24 Jan 2022, peer-reviewed, 7 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

In vitro Potential Antiviral SARS-CoV-19- Activity of Natural Product Thymohydroquinone and Dithymoquinone from Nigela sativia

Esharkawy et al., Bioorganic Chemistry, doi:10.1016/j.bioorg.2021.105587 (In Vitro)

In Vitro and In Silico study of nigella sativa components, showing anti-SARS-CoV-2 activity at non-cytotoxic nanomolar concentrations for thymohydroquinone with selectivity index 1.4.

Esharkawy et al., 1 Jan 2022, peer-reviewed, 3 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

Nigellidine (Nigella sativa, black-cumin seed) docking to SARS CoV-2 nsp3 and host inflammatory proteins may inhibit viral replication/transcription

Banerjee et al., Natural Product Research, doi:10.1080/14786419.2021.2018430

In Silico study showing nigella sativa docking to SARS CoV-2 Nsp3 and host inflammatory proteins, which may inhibit viral replication.

Banerjee et al., 22 Dec 2021, peer-reviewed, 6 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

Identifying the Most Potent Dual-Targeting Compound(s) against 3CLprotease and NSP15exonuclease of SARS-CoV-2 from Nigella sativa: Virtual Screening via Physicochemical Properties, Docking and Dynamic Simulation Analysis

Rizvi et al., Processes, doi:10.3390/pr9101814

In Silico study predicting that nigella sativa component dithymoquinone has good affinity and stability against SARS-CoV-2 3CL^pro and NSP15, suggesting potential benefits for COVID-19 treatment.

Rizvi et al., 13 Oct 2021, peer-reviewed, 10 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

Efficacy of Persian medicine herbal formulations (capsules and decoction) compared to standard care in patients with COVID-19, a multicenter open-labeled, randomized, controlled clinical trial

Karimi et al., Phytotherapy Research, doi:10.1002/ptr.7277

RCT 358 hospitalized patients in Iran, 184 receiving treatment with a combination of nigella sativa and several other herbal medicines, showing shorter hospitalization time and improved recovery with treatment. IR.TUMS.VCR.REC.1399.024.

risk of death, 50.8% lower, RR 0.49, p = 0.45, treatment 2 of 192 (1.0%), control 4 of 189 (2.1%), NNT 93.

risk of ICU admission, 60.6% lower, RR 0.39, p = 0.28, treatment 2 of 192 (1.0%), control 5 of 189 (2.6%), NNT 62.

hospitalization time, 70.0% lower, HR 0.30, p < 0.001, treatment 184, control 174, Cox proportional hazards, primary outcome.

fever, 66.5% lower, OR 0.33, p = 0.001, treatment 184, control 174, inverted to make OR<1 favor treatment, RR approximated with OR.

dyspnea, 13.7% lower, OR 0.86, p < 0.001, treatment 184, control 174, inverted to make OR<1 favor treatment, RR approximated with OR.

Karimi et al., 4 Oct 2021, Randomized Controlled Trial, Iran, peer-reviewed, 37 authors, study period March 2020 - July 2020, this trial uses multiple treatments in the treatment arm (combined with several herbal medicines) - results of individual treatments may vary.

Identification of SARS-CoV-2 RNA-dependent RNA polymerase inhibitors from the major phytochemicals of Nigella sativa: An in silico approach

Mir et al., Saudi Journal of Biological Sciences, doi:10.1016/j.sjbs.2021.09.002

In Silico study identifying phytochemicals from nigella sativa (𝛼-hederin, dithymoquinone, negillicine, and negillidine) as potential SARS-CoV-2 RNA-dependent RNA polymerase inhibitors.

Mir et al., 8 Sep 2021, peer-reviewed, 11 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

Nigella sativa for the treatment of COVID-19: An open-label randomized controlled clinical trial

Koshak et al., Complementary Therapies in Medicine, doi:10.1016/j.ctim.2021.102769

RCT 183 mild COVID-19 outpatients in Saudi Arabia, 91 treated with Nigella Sativa, showing lower hospitalization and faster recovery with treatment. 500mg Nigella Sativa oil (MARNYS Cuminmar) twice daily for 10 days. NCT04401202.

risk of hospitalization, 74.7% lower, RR 0.25, p = 0.37, treatment 1 of 91 (1.1%), control 4 of 92 (4.3%), NNT 31.

risk of no recovery, 42.7% lower, RR 0.57, p < 0.001, treatment 34 of 91 (37.4%), control 60 of 92 (65.2%), NNT 3.6.

Koshak et al., 15 Aug 2021, Randomized Controlled Trial, Saudi Arabia, peer-reviewed, 10 authors, trial NCT04401202 (history).

Therapeutic Potential of Thymoquinone and Its Nanoformulations in Pulmonary Injury: A Comprehensive Review

Al-Gabri et al., International Journal of Nanomedicine, doi:https://doi.org/10.2147/IJN.S314321 (Review)

Review of thymoquinone (a component of nigella sativa) research, antioxidant, anti-inflammatory, and antineoplastic properties, application to lung conditions, and the potential advantages of nanoformulations on drug solubility, cellular absorption, and drug delivery to lung tissue target sites.

Al-Gabri et al., 27 Jul 2021, peer-reviewed, 11 authors.

The potential role of thymoquinone in preventing the cardiovascular complications of COVID-19

Ahmad et al., Vascular Pharmacology, doi:10.1016/j.vph.2021.106899 (Review)

Review of the potential role of thymoquinone (a component of nigella sativa) in minimizing cardiovascular complications of COVID-19.

Ahmad et al., 23 Jul 2021, peer-reviewed, 3 authors.

The role of thymoquinone, a major constituent of Nigella sativa, in the treatment of inflammatory and infectious diseases

Shad et al., Clinical and Experimental Pharmacology and Physiology, doi:10.1111/1440-1681.13553 (Review)

Review of the pharmacological properties of nigella sativa and thymoquinone and application for a variety of diseases, focusing on recent studies of the anti-inflammatory and antiviral properties that are promising for diseases including COVID-19.

Shad et al., 23 Jul 2021, peer-reviewed, 3 authors.

Exploring the Potency of Nigella sativa Seed in Inhibiting SARS-CoV-2 Main Protease Using Molecular Docking and Molecular Dynamics Simulations

Hardianto et al., Indonesian Journal of Chemistry, doi:10.22146/ijc.65951

In Silico study showing nigella sativa metabolites binding to SARS-CoV-2 M^pro.

Hardianto et al., 12 Jul 2021, peer-reviewed, 5 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

Patients’ Behavior Regarding Dietary or Herbal Supplements before and during COVID-19 in Saudi Arabia

Aldwihi et al., International Journal of Environmental Research and Public Health, doi:10.3390/ijerph18105086

Retrospective survey-based analysis of 738 COVID-19 patients in Saudi Arabia, showing lower hospitalization with vitamin C, turmeric, zinc, and nigella sativa, and higher hospitalization with vitamin D. For vitamin D, most patients continued prophylactic use. For vitamin C, the majority of patients continued prophylactic use. For nigella sativa, the majority of patients started use during infection. Authors do not specify the fraction of prophylactic use for turmeric and zinc.

risk of hospitalization, 24.0% lower, RR 0.76, p = 0.09, treatment 85 of 345 (24.6%), control 152 of 393 (38.7%), NNT 7.1, adjusted, OR converted to RR, multivariable.

Aldwihi et al., 11 May 2021, retrospective, Saudi Arabia, peer-reviewed, survey, mean age 36.5, 8 authors, study period August 2020 - October 2020.

Active-site Molecular docking of Nigellidine to nucleocapsid/Nsp2/Nsp3/MPro of COVID-19 and to human IL1R and TNFR1/2 may stop viral-growth/cytokine-flood, and the drug source Nigella sativa (black cumin) seeds show potent antioxidant role in experimental rats

Maiti et al., Research Square, doi:10.21203/rs.3.rs-26464/v1 (Preprint)

In Silico and animal study of nigella sativa and component nigellidine, showing nigellidine binding activity for several important SARS-CoV-2 proteins and for relevant host receptors; and that black cumin seed extract was antioxidative, hepato- and reno-protective in rats.

Maiti et al., 5 May 2021, preprint, 5 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

In silico identification of compounds from Nigella sativa seed oil as potential inhibitors of SARS-CoV-2 targets

Duru et al., Bulletin of the National Research Centre, doi:10.1186/s42269-021-00517-x

In Silico study of compounds from Nigella Sativa oil. Authors identify component phytochemicals with gas chromatography-mass spectrometry and analyze binding affinity with SARS-CoV-2 targets. Caryophyllene oxide, α-bergamotene, and β-bisabolene were identified as promising candidates for inhibition.

Duru et al., 12 Mar 2021, peer-reviewed, 3 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

Response to Nigella sativa in Patients with Confirmed and Suspected COVID-19

Fetian et al., Healthbook Times, doi:10.36000/hbT.2021.01.001

Retrospective 35 patients treated with Nigella Sativa showing good outcomes and relatively fast recovery. There was no control group.

Fetian et al., 4 Mar 2021, peer-reviewed, 4 authors.

Preventive Value of Black Seed in People at Risk of Infection with COVID-19

Al-Haidari et al., Pakistan Journal of Medical and Health Sciences, 15:1

Prophylaxis study with 376 mostly high-risk patients, 188 treated with nigella sativa, showing significantly lower cases with treatment. Black seeds 40mg/kg orally once daily.

risk of symptomatic case, 62.2% lower, RR 0.38, p < 0.001, treatment 68 of 188 (36.2%), control 180 of 188 (95.7%), NNT 1.7.

Al-Haidari et al., 31 Jan 2021, prospective, Iraq, peer-reviewed, 3 authors.

Clinical Trial of Black Seeds Against COVID – 19 in Kirkuk City / Iraq

Al-Haidari et al., Indian Journal of Forensic Medicine & Toxicology, 15:3 (date from earlier preprint)

Open-label RCT with 419 patients in Iraq, 160 treated with Nigella Sativa, showing lower mortality and severe cases with treatment. Black seeds 40mg/kg orally once daily for 14 days.

risk of death, 95.8% lower, RR 0.04, p = 0.001, treatment 0 of 160 (0.0%), control 14 of 259 (5.4%), NNT 18, relative risk is not 0 because of continuity correction due to zero events.

risk of severe case, 92.6% lower, RR 0.07, p < 0.001, treatment 2 of 160 (1.2%), control 44 of 259 (17.0%), NNT 6.4.

Al-Haidari et al., 31 Jan 2021, Randomized Controlled Trial, Iraq, peer-reviewed, 3 authors.

Honey and Nigella sativa against COVID-19 in Pakistan (HNS-COVID-PK): A multi-center placebo-controlled randomized clinical trial

Ashraf et al., medRxiv, doi:10.1101/2020.10.30.20217364 (Preprint)

RCT with 157 patients treated with honey and nigella sativa, and 156 control patients, showing significantly faster recovery and viral clearance.

Honey (1gm/kg/day) plus encapsulated nigella sativa seeds (80mg/kg/day) orally in 2-3 divided doses daily for up to 13 days.

risk of death, 81.9% lower, RR 0.18, p = 0.01, treatment 2 of 157 (1.3%), control 11 of 156 (7.1%), NNT 17, all cases.

risk of death, 67.1% lower, RR 0.33, p = 0.49, treatment 0 of 107 (0.0%), control 1 of 103 (1.0%), NNT 103, relative risk is not 0 because of continuity correction due to zero events, moderate cases.

risk of death, 78.8% lower, RR 0.21, p = 0.03, treatment 2 of 50 (4.0%), control 10 of 53 (18.9%), NNT 6.7, severe cases.

risk of no recovery, 83.6% lower, HR 0.16, p < 0.001, treatment 107, control 103, inverted to make RR<1 favor treatment, moderate cases.

risk of no recovery, 75.2% lower, HR 0.25, p < 0.001, treatment 50, control 53, inverted to make RR<1 favor treatment, severe cases.

risk of no viral clearance, 81.9% lower, HR 0.18, p < 0.001, treatment 107, control 103, inverted to make RR<1 favor treatment, moderate cases.

risk of no viral clearance, 76.9% lower, HR 0.23, p < 0.001, treatment 50, control 53, inverted to make RR<1 favor treatment, severe cases.

Ashraf et al., 3 Nov 2020, Randomized Controlled Trial, Pakistan, preprint, 48 authors, this trial uses multiple treatments in the treatment arm (combined with honey) - results of individual treatments may vary, trial NCT04347382 (history) (HNS-COVID-PK).

Promising preventive and therapeutic effects of TaibUVID nutritional supplements for COVID-19 pandemic: towards better public prophylaxis and treatment (A retrospective study)

El Sayed et al., Am J Blood Res., doi:

Small retrospective study of 20 patients in Egypt suggesting benefits of TaibUVID (nigella sativa, chamomile and honey) treatment.

El Sayed et al., 15 Oct 2020, Egypt, peer-reviewed, 18 authors, this trial uses multiple treatments in the treatment arm (combined with chamomile and honey) - results of individual treatments may vary.

Potential influence of Nagella sativa (Black cumin) in reinforcing immune system: A hope to decelerate the COVID-19 pandemic

Kulyar et al., Phytomedicine, doi:10.1016/j.phymed.2020.153277 (Review)

Review of immune-regulating, anti-inflammatory, and antioxidant benefits of nigella sativa, and potential benefits for COVID-19.

Kulyar et al., 10 Jul 2020, peer-reviewed, 6 authors.

Covid-19 and thymoquinone: Connecting the dots

Ahmad et al., Phytotherapy Research, doi:10.1002/ptr.6793 (Review) (Preprint)

Review of the potential benefits of thymoquinone (a component of nigella sativa) for COVID-19, recommending clinical trials.

Ahmad et al., 26 Jun 2020, preprint, 4 authors.

Identification of Compounds from Nigella Sativa as New Potential Inhibitors of 2019 Novel Coronasvirus (Covid-19): Molecular Docking Study

Bouchentouf et al., ChemRxiv, doi:10.26434/chemrxiv.12055716.v1 (Preprint)

In Silico study of compounds from nigella sativa identifying nigellidine and α-Hederin as potential compounds that inhibit SARS-CoV-2.

Bouchentouf et al., 2 Apr 2020, preprint, 2 authors.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.