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Synergism Among Nutraceuticals: Black Seed Oil, Omega-3, Astaxanthin & More

Black Seed Oil Black Seed Oil
Longevity By Nature
 
Kaneka

I previously wrote an article on “Evidence-Based Uses of Standardized Black Seed Oil” for the June 2023 issue of Vitamin Retailer (Natural Practitioner’s sister publication). In that article, I highlighted the research demonstrating the effectiveness of black seed oil (BSO) standardized for its thymoquinone content. In this article, I’m going to take it a step further and examine that synergistic relationship that BSO has with other nutraceuticals, including omega-3 fatty acids, vitamin D, astaxanthin, CBD and Pycnogenol, as well as the carotenoids beta-carotene and lutein. But first, let’s start with a brief review of BSO by itself.

Background

Black cumin seed, or black seed for short (Nigella sativa) has been used medicinally in the Middle East and Southeast Asia for more than 2,000 years,1,2 and has been used throughout the world medicinally and as a food seasoning for centuries. Greek pharmaco-botanist, Dioscorides (40-90 CE) described the use of black seeds from a plant now thought to be N. sativa as a remedy for breathing difficulties, inflammatory conditions, skin ailments and parasites.3

Research on Non-standardized BSO

Most of the therapeutic properties of BSO are attributed to its essential oil constituent, thymoquinone (TQ). Research on non-standardized BSO, which requires a higher dose of up to 2.3 g, compared to 500 mg with the standardized form, has demonstrated effectiveness in reducing body weight,4 blood pressure and blood glucose levels,5-7 improving endothelial/arterial function and reducing oxidation,8,9 improving lipid profiles and C-reactive protein (inflammation marker)10 reducing osteoarthritis symptoms,11 promoting faster recovery of symptoms for patients with mild COVID-19 infection,12 improving asthma symptoms,13 and reduced dyspepsia severity and the rate of H. pylori infection.14

Research on Standardized BSO

When BSO standardized for 3 percent TQ (ThymoQuin black seed oil) was used at 500 mg, human clinical research demonstrated effectiveness for reducing systolic blood pressure by 11.2 percent and diastolic by 12.2 percent in six weeks. When evaluating the initial effect of ThymoQuin, 48 hours after initial treatment, a significant decrease in blood pressure was observed in all patients with no increase in pulse rate.15 Likewise, a four-week, placebo-controlled, double-blind study16 with the same standardized BSO reported significantly fewer upper respiratory tract complaints (62 percent lower) and better overall well-being (11 percent improvement), as well as lower cortisol (44 percent less) and superior microbiome diversity (66 percent higher Streptococcus thermophilus, 8 percent higher microbiome composite score) compared to placebo.

Research on Topical Standardized BSO

In addition to oral supplementation with standardized BSO, there have also been studies demonstrating benefits with topical application, branded as B’utyQuin for cosmetic use. In a randomized, blinded, placebo-controlled trial,17 3 percent BSO cream was fond to improve skin firmness, elasticity, hydration and luminosity compared to placebo. In another blinded, controlled study,18 5 percent BSO scalp serum resulted in statistically significant decreases in erythema (reddening) and scaling scores.

Synergism With Other Nutraceuticals

In this context, synergism is the interaction or cooperation of two or more substances to produce a combined effect greater than the sum of their separate effects. Certainly, it is not unusual to find a synergistic relationship between nutrients or other nutraceuticals. Nevertheless, the term “synergistic” is often used for a combination of nutraceuticals when there isn’t any scientific data supporting any synergistic effect of the combination. In the case of BSO, however, there is indeed scientific validation for a synergistic effect with other specific nutraceuticals.

Omega-3 Fatty Acids

In a cell culture study19 using peritoneal macrophages collected from mice, ThymoQuin caused a dose dependent anti-inflammatory effect detected by inhibition of NO (nitric oxide) production in macrophages. The addition of low concentration of omega-3 fatty acids caused a significant synergistic inhibition of NO production. A higher concentration of omega-3s caused an additive effect. The experiment was repeated with a lower concentration of omega-3s in order to achieve a better synergism. The addition of low concentration of omega-3s caused a significant synergistic inhibition of NO production with ThymoQuin. In conclusion, a low concentration of ThymoQuin together with omega-3 fatty acids resulted in a significant anti-inflammatory effect.

Excessive fat accumulation in white adipose tissue (WAT) results in chronic low-grade inflammation, which is the major cause of obesity-associated insulin resistance and consequent metabolic disease. The development of beige adipocytes in WAT (browning of WAT) increases energy expenditure and has been considered as a novel strategy to counteract obesity. Consequently, research20 was conducted where murine preadipocyte cells were cultured to investigate the effects of TQ and omega-3s (ω3) on the browning of WAT. In addition, mice were fed a high-fat diet (HFD), supplemented with 0.75 percent TQ, and 2 percent ω3 in combination for eight weeks. Results were that TQ and ω3 reduced fat droplet size in preadipocyte cells and increased hallmarks of beige adipocytes. In the adipose tissue of mice, TQ and ω3 treatment attenuated levels of inflammatory adipokines, and diminished adipocyte hypoxia (which would otherwise induce insulin resistance in fat cells). In conclusion, the enhanced browning of WAT from TQ treatment in combination with ω3 may play an important role in decreasing obesity-associated insulin resistance and in reducing the chronic inflammatory state of obesity.

A placebo-controlled, human clinical study21 was conducted in which the effects of 500 mg of BSO plus 1,500 mg fish oil (providing 1,200 mg ω3) or placebo were evaluated on upper-respiratory tract complaints (URTCs) and psychological mood state in 35 male and female runners during a four-week supplementation period (three weeks before and one week following a marathon or half-marathon competition). Subjective and objective measures were collected before and after supplementation. Results were that subjects in the supplementation group experienced significantly fewer upper-respiratory tract complaints (URTCs) and better overall well-being, as well as higher ω3 blood levels, lower cortisol and superior microbiome indices, compared to placebo. These results suggest that the combination of BSO plus fish oil may improve immune system vigilance and overall well-being following the stress of endurance training and competition, possibly via improvements in the microbiome and gut-immune-axis.

Vitamin D3

An in-vitro and mouse study22 was conducted in which the additive effects of TQ and vitamin D3 were examined on immune-mediated inflammation of mesenchymal stem cells (MSCs)—found in bone marrow and important for making and repairing skeletal tissues. MSCs were treated with TQ and vitamin D3, then compared to control for seven days. Their effects on MSC proliferation, levels of inflammatory biomarkers, changes in fat droplet number and size, adipocyte differentiation, mitochondrial biogenesis and stem cell function were examined. Mice fed a high-fat diet for 23 weeks were then divided into three groups: Lean controls, HFD with no intervention and HFD treated with TQ, for an additional eight weeks, and hepatic inflammation and ANG-1 levels (i.e., a protein important in vascular development) were examined. The results were that TQ increased the levels of Mfn-2 and PGC-1α—proteins that play a role in mitochondrial biogenesis. The addition of vitamin D3 enhanced these effects. Also, TQ increased ANG-1 and decreased the inflammatory cytokine TNFα. ANG-1 action on MSCs directly affected MSC differentiation but not proliferation while improving immune function with a reduction in TNFα levels. HFD Mice treated with TQ all showed a decrease in fat droplet size and number. In conclusion, TQ increased stem cell (MSC) proliferation and significantly reduces the inflammatory state, both alone and with vitamin D3, which enhanced effects. TQ had a powerful effect on MSC differentiation and expansion with a reduction in inflammation.

Astaxanthin

An in-vitro study23 was conducted examining the effect of a combination of BSO 3 percent (ThymoQuin) and astaxanthin on the inhibition of NO in macrophages which, as previously noted, is indicative of an anti-inflammatory effect. The result was that the combination effectively and exponentially increased the NO inhibition over BSO and astaxanthin alone.

In a design similar to that of the previously described BSO and fish oil study, this study24 evaluated the effects of a combination of 500 mg BSO and 8 mg astaxanthin on upper-respiratory tract complaints (URTCs) and psychological mood state in 32 male and female runners or a placebo daily during a four-week supplementation period (three weeks before and one week following a marathon or half-marathon competition). Subjective and objective measures were collected before and after supplementation. Results were that subjects in the supplementation group experienced significantly fewer URTCs and better overall well-being, as well as lower cortisol and superior microbiome indices, compared to placebo. Likewise, these results suggest that the combination of BSO plus astaxanthin may improve immune system vigilance and overall well-being following the stress of endurance training and competition, possibly via improvements in the microbiome and gut-immune-brain-axis.

CBD

In a cell culture study25 using peritoneal macrophages collected from mice, a low 3 percent dose of ThymoQuin caused a dose dependent anti-inflammatory effect detected by inhibition of NO production in macrophages. The addition of low concentration of CBD caused a significant synergistic inhibition of NO production. A higher concentration of CBD created a low cell survival death. The experiment was repeated with a lower concentration of CBD in order to achieve a better synergism. The addition of low concentration of CBD caused a significant synergistic inhibition of NO production with ThymoQuin. In conclusion, a low concentration of ThymoQuin together with a low dosage of CBD resulted in a significant anti-inflammatory effect.

As with the in-vitro BSO and astaxanthin study, another in-vitro study26 was conducted examining the effect of a combination of BSO 3 percent (ThymoQuin) and CBD 8 percent on the inhibition of NO in. The result was that the combination effectively and exponentially increased the NO inhibition over BSO and CBD alone.

Pycnogenol

As with the in-vitro BSO and astaxanthin study, another in-vitro study27 was conducted examining the effect of a combination of BSO 3 percent (ThymoQuin) and Pycnogenol on the inhibition of NO in. The result was that the combination effectively and exponentially increased the NO inhibition over BSO and Pycnogenol alone.

Beta-carotene & Lutein

As with the in-vitro BSO and astaxanthin study, another in-vitro study28 was conducted examining the effect of a combination of BSO 3 percent (ThymoQuin) and beta-carotene or lutein on the inhibition of NO. The results were that the combination of BSO and beta-carotene, and the combination of BSO and lutein also effectively and exponentially increased the NO inhibition over BSO and or either carotenoid alone.

Conclusion

By itself, BSO has a body of research demonstrating its effectiveness in various areas of health and wellness, including its anti-inflammatory effects. When BSO, especially as ThymoQuin, is combined with omega-3 fatty acids, vitamin D, astaxanthin, CBD and Pycnogenol, as well as the carotenoids beta-carotene and lutein, there is a significant synergistic impact on efficacy. Consequently, formulations win which BSO is included with these other nutraceuticals are likely to yield greater overall results, particularly from an anti-inflammatory and improved immune response perspectives.

References:

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2 Germer R. Handbuch der altagyptischen Heilpflanzen. Wiesbad, Germany: Otto Harrassowitz; 2008.

3 Beck LY. De Materia medica by Pedanius Dioscorides. Hildesheim, Germany: Olms-Weidman; 2005.

4 Mousavi SM, Sheikhi A, Varkaneh HK, Zarezadeh M, Rahmani J, Milajerdi A. Effect of Nigella sativa supplementation on obesity indices: a systematic review and meta-analysis of randomized controlled trials. Complement Ther Med. June 2018;38:48-57.

5 Tavakoli-Rouzbehani OM, Abbasnezhad M, Kheirouri S, Alizadeh M. Effects of Nigella sativa oil supplementation on selected metabolic parameters and anthropometric indices in patients with coronary artery disease: A randomized, double-blind, placebo-controlled clinical trial. Phytother Res. 2021 Jul;35(7):3988-3999.

6 Fallah Huseini H, Amini M, Mohtashami R, Ghamarchehre ME, Sadeqhi Z, Kianbakht S, Fallah Huseini A. Blood pressure lowering effect of Nigella sativa L. seed oil in healthy volunteers: a randomized, double-blind, placebo-controlled clinical trial. Phytother Res. 2013 Dec;27(12):1849-53.

7 Hadi S, Daryabeygi-Khotbehsara R, Mirmiran P, McVicar J, Hadi V, Soleimani D, Askari G. Effect of Nigella sativa oil extract on cardiometabolic risk factors in type 2 diabetes: A randomized, double-blind, placebo-controlled clinical trial. Phytother Res. 2021 Jul;35(7):3747-3755.

8 Tavakoli-Rouzbehani OM, Abbasnezhad M, Kheirouri S, Alizadeh M. Efficacy of Nigella sativa oil on endothelial function and atherogenic indices in patients with coronary artery diseases: A randomized, double-blind, placebo-control clinical trial. Phytother Res. 2022 Dec;36(12):4516-4526.

9 Emamat H, Mousavi SH, Kargar Shouraki J, Hazrati E, Mirghazanfari SM, Samizadeh E, Hosseini M, Hadi V, Hadi S. The effect of Nigella sativa oil on vascular dysfunction assessed by flow-mediated dilation and vascular-related biomarkers in subject with cardiovascular disease risk factors: A randomized controlled trial. Phytother Res. 2022 May;36(5):2236-2245.

10 Kooshki A, Tofighiyan T, Rastgoo N, Rakhshani MH, Miri M. Effect of Nigella sativa oil supplement on risk factors for cardiovascular diseases in patients with type 2 diabetes mellitus. Phytother Res. 2020 Oct;34(10):2706-2711.

11 Huseini HF, Mohtashami R, Sadeghzadeh E, Shadmanfar S, Hashem-Dabaghian F, Kianbakht S. Efficacy and safety of oral Nigella sativa oil for symptomatic treatment of knee osteoarthritis: A double-blind, randomized, placebo-controlled clinical trial. Complement Ther Clin Pract. 2022 Nov;49:101666.

12 Koshak AE, Koshak EA, Mobeireek AF, Badawi MA, Wali SO, Malibary HM, Atwah AF, Alhamdan MM, Almalki RA, Madani TA. Nigella sativa for the treatment of COVID-19: An open-label randomized controlled clinical trial. Complement Ther Med. 2021 Sep;61:102769.

13 Koshak A, Wei L, Koshak E, Wali S, Alamoudi O, Demerdash A, Qutub M, Pushparaj PN, Heinrich M. Nigella sativa Supplementation Improves Asthma Control and Biomarkers: A Randomized, Double-Blind, Placebo-Controlled Trial. Phytother Res. 2017 Mar;31(3):403-409.

14 Mohtashami R, Huseini HF, Heydari M, Amini M, Sadeqhi Z, Ghaznavi H, Mehrzadi S. Efficacy and safety of honey based formulation of Nigella sativa seed oil in functional dyspepsia: A double blind randomized controlled clinical trial. J Ethnopharmacol. 2015 Dec 4;175:147-52.

15 Bush B, Peña T, Bush R, et al. Effects of Standardized Black Seed Oil Cold Press Supplement Over A Six Week Period on Blood Pressure and Heart Rate in Healthy Patients: A Nonrandomized Clinical Trial. Food Sci Nutr Res. 2020; 3(1): 1-5.

16 Talbott SM, Talbott JA. Effect of ThymoQuin Black Cumin Seed Oil as a Natural Immune Modulator of Upper-Respiratory Tract. Complaints and Psychological Mood State. Unpublished, nd.

17 von Oppen-Bezalel L, Jurenka JS. Mitochondrial Revitalization for Skin Rejuvenation by a Proprietary, Cold-Pressed Nigella sativa Seed (Black Cumin) Oil Standardized to 3 percent Thymoquinone. Cosmetics & Toiletries. June 10, 2022. Retrieved March 31, 2023 from www.cosmeticsandtoiletries.com/cosmetic-ingredients/natural-sustainable/article/22236404/trinutra-20871-mitochondrial-revitalization-for-skin-rejuvenation-coldpressed-nigella-sativa-seed-oil-standardized-to-3-thymoquinone.

18 von Oppen-Bezalel L, Jurenka JS. Irritated, Itchy, Scaly, Seborrheic Scalp: Causes and Relief with a Proprietary, Cold-Pressed Nigella sativa (Black Seed) Oil Standardized to 3 percent Thymoquinone. SOFW Journal. July 8, 2022. Retrieved March 31, 2023 from www.sofw.com/en/sofw-journal/articles-en/48-personal-care/3101-irritated-itchy-scaly-seborrheic-scalp-causes-and-relief-with-a-proprietary-cold-pressed-nigella-sativa-black-seed-oil-standardized-to-3-thymoquinone.

19 Solomonov Y, Hadad N, Levy R. The synergistic anti-inflammatory effect of ThymoQuin™ and Omega 3 from KinOmega. Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev. January 2018.

20 Shen HH, Peterson SJ, Bellner L, Choudhary A, Levy L, Gancz L, Sasson A, Trainer J, Rezzani R, Resnick A, Stec DE, Abraham NG. Cold-Pressed Nigella sativa Oil Standardized to 3 percent Thymoquinone Potentiates Omega-3 Protection against Obesity-Induced Oxidative Stress, Inflammation, and Markers of Insulin Resistance Accompanied with Conversion of White to Beige Fat in Mice. Antioxidants (Basel). 2020 Jun 4;9(6):489.

21 Talbott SM, Talbott JA. Black Cumin Seed Oil Plus Fish Oil Combination Modulates Gut-Immune-Axis. EC Nutrition. 2022; 17.7: 18-27.

22 Yuen K, Alex A, Raffaelle M, Shen H, Ospino J, Bellner L, Abraham NG, Peterson SJ. Beneficial Effect of 3 percent Thymoquinone on Stem Cell-Mediated Improvement in Immune System and Anti-Inflammatory Function. J Nutr Food Sci. 2021; 3(3): 63-74.

23 Solomonov Y, Hadad N, Levy R. Report 8 ketzach + carotenoids. Unpublished. 26.12.18.

24 Talbott SM, Talbott JA. Combination of Black Cumin Seed Oil and Astaxanthin Supports Gut-Immune-Brain-Axis and Improves Mood. Scho J Food & Nutr. 4(3)-2022.

25 Solomonov Y, Hadad N, Levy R. The synergistic anti-inflammatory effect of ThymoQuin and 15 percent CBD from Hemp Oil. Department of clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev. May 2019.

26 Solomonov Y, Hadad N, Levy R. Report 8 CBD + Pycnogenol. Unpublished. 7.5.19.

27 Solomonov Y, Hadad N, Levy R. Report 8 CBD + Pycnogenol. Unpublished. 7.5.19.

28 Solomonov Y, Hadad N, Levy R. Report 8 ketzach + carotenoids. Unpublished. 26.12.18.

Gene Bruno, MS, MHS, Professor Emiritus of Nutraceutical Science, is a nutritionist, herbalist, writer and educator. For more than 40 years he has educated and trained natural product retailers and health care professionals, has researched and formulated natural products for dozens of dietary supplement companies, and has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines and peer-reviewed publications. He can be reached at eugenejbruno@gmail.com.