Tuesday, January 6, 2015

Reader Question: Are Black Seeds (Nigella Sativa), Their Oil, Ointments & More Good For Me? What do the Studies Say?

Nigella sativa is available in form of seeds, oils and all sorts of ointments and for many of them there are studies suggesting that they work.
SuppVersity reader Amaan Mueen asks on Facebook: "In traditional Oriental medicine it's said that blackseed is a cure for everything except death, is there any truth to that?" I probably don't give away too much, when I tell you that blackseed (also "black seed") aka "nigella sativa" is not going to cure everything, but death, but that does not mean that modern Western medicine has not been able to confirm what Oriental "doctors" have known for centuries.

In the following I am going to present an allegedly cursory overview of the existing evidence with a focus on those health benefits that could be relevant for the average and extra-ordinary SuppVersity reader.
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  • General anti-oxidant effects - The complete oil of N. sativa, as well as thymoquinone (the main compound of the essential oil) have been shown to significantly reduce non-enzymatic lipid peroxidation in liposomes (Houghton. 1995). Significant anti-oxidant effects have also been observed for other compounds isolated from N. sativa, uncluding thymoquinone, carvacol, t-anethole and 4-terpineol.

    Figure 1: The tymoquinone rich fraction of blackseed (TQRF-X) has dose dependent (L,M,H) effects on antioxidant enzyems in hypercholesterolemic (Ismail. 2010).
    These compounds were found in a series of other in vitro tests to have variable antioxidant, but no pro-oxidant properties.

    Most importantly, though, the different compounds in the oil were found to act in a synergistic manner (i.e. more than the mere summation of the actions of the individual compounds). This stresses the importance of using the whole oil (or the crude extract) of the seeds in pharmacological studies.

    As Ali and Blunden point out in their review of the literature, "the antioxidant property of N. sativa is multifactorial, [but] it does not seem to involve iron-complexing activity (Ali. 2003). It rather appears as if its general ability to scavenge free radicals, which may be, at least partially, the basis of many human diseases and conditions, could be at the heart of its ability to protect, for example, against CCl4 hepatotoxicity (Nagi. 1999), liver fibrosis and cirrhosis (Türkdogan. 2000), and hepatic damage induced by Schistosoma mansoni infection (Mahmoud. 2002).
  • Antiinflammatory and analgesic actions -It's one thing to scavenge free radicals. It's yet a completely different thing to effectively reduce the inflammation that's often, but not always triggered by the presence of free radicals. Against that background it's important to note that an aqueous extract from nigella sativa exhibits strong anti-inflammatory effects, as well (Al-Ghamdi, 2001). Using carrageenan-induced paw oedema as a model of inflammation, and the hot plate reaction time as a model of nociception, the extract was found to possess significant antiinflammatory and analgesic (=pain reducing) action.

    As Ali & Blunden (2003) point out, this finding lends some credence to the folk medicinal use of the plant as an antiinflammatory and analgesic substance, and also confirms previous reports on the antinociceptive (Abdel-Fattah. 2000) and antiinflammatory (Mutabagani. 1997) effects of N. sativa oil and its major component, thymoquinone, in mice.

    The possible mechanism by which N. sativa exerts its antiinflammatory action has been studied. Thymoquinone has been shown to be a potent inhibitor of eicosanoid generation, namely thromboxane B2 and leucotrienes B4, by inhibiting both cyclooxygenase and lipooxygenase, respectively (Houghton. 1995). Interestingly, it was found that the fixed oil of N. sativa had both antioxidant and anti-eicosanoid effects greater than thymoquinone, which is its active constituent (Houghton. 1995)
Chemical structure of some of the main potentially bioactive compounds in Nigella sativa (Paarakh. 2010).
What's actually in the seeds? N. sativa seeds contain 36%–38% fixed oils, proteins, alkaloids, saponin and 0.4%–2.5% essential oil (Lautenbucher, 1997). The fixed oil is composed mainly of unsaturated fatty acids, including the unusual C20:2 arachidic and eicosadienoic acids (Houghton. 1995). The hitherto discovered active ingredients of the essential oil are thymoquinone  (27.8%–57.0%), ρ-cymene (7.1%–15.5%), carvacrol (5.8%–11.6%), t-anethole (0.25%–2.3%), 4-terpineol (2.0%–6.6%) and longifoline (1.0%–8.0%).

In addition, it contains four alkaloids and several monodesmosidic triterpene saponins. What? Yeah... unfortunately, we know only of few of the (potentially) active ingredients and even less about what exactly they do.
  • Anti-Cancer Effect - In an in-vitro study from the late 1990s researchers from the Tobacco and Health Research Institute in Lexington were able to show that the thymoquinone (TQ) and dithymoquinone (DIM) content of nigella sativa have the astonishing ability to kill several parental and multi-drug resistant (MDR) human tumor cell lines (Worthen. 1997).
    Figure 2: A schematic diagram showing major molecular targets of TQ. As an anticancer agent, TQ inhibits the activity of CYP enzymes, which are involved in metabolic activation carcinogens, and induces the expression and activities of cytoprotective enzymes by activating Nrf2 signaling. TQ selectively induces tumor cell death in an ROS-dependent manner following both intrinsic and extrinsic pathways of apoptosis. TQ exerts anti-proliferative, anti-inflammatory, anti-migratory, anti-invasive and anti-metastatic effects by blocking the activation of NF-κB- and STAT3-regulated gene products (Kundu. 2014).
    In spite of the fact that there are as of yet no studies that show that humans were cured with blackseed, recent studies have shown that Thymoquinone, a component of Nigella sativa, decreases oxidative DNA damage in a rat model of mammary cancer (Sindi. 2014) and protect the brain, liver and other organs from radiation induced damage during cancer therapy (Ahlatci. 2014; Cikman. 2014). So, even if it were not for its established cytotoxic effects in various human cancer cells (e.g. Liver, Khan. 2014; Kidney, Tabasi. 2014; Prostate & Breast Cancer, Schneider-Stock. 2014; Cervix, Ichwan. 2014; etc.), it would still make sense to use black seed extracts as antioxidants during radiation and as studies indicate also chemotherapy (Pace. 2003; Almog. 2014).
  • Anti-allergic effects - In a study from 2003 Kalus et al. observed significant reductions in subjective feeling of allergic symptoms in 152 patients with allergic diseases (allergic rhinitis, bronchial asthma, atopic eczema) who were treated with Nigella sativa oil, given in capsules at a dose of 40 to 80 mg/kg/day.

    Figure 3: The addition of blackseeds at a dosage of 2g/day propels the beneficial effects of subcutaneous allergen-specific immunotherapy on polymorphonuclear leukocyte (PMN) function in 24 patients sensitive to house dust mites with allergic rhinitis (Işık. 2010)
    Other studies confirm that Nigella sativa can reduce the peripheral blood eosinophil count, IgG1 and IgG2a, cytokine profiles and lung inflammation in murine model of allergic asthma (Abbas. 2004) that are equal to the corticosteriod dexamethasone and scientists from the Gaziosmanpasa University Medical Faculty say that "N. sativa display its antioxidant and regulatory effects via inflammatory cells rather than the host tissue (brain and medulla spinalis)" in a rodent model of experimental allergic encephalomyelitis (Ozugurlu. 2005). Effects that were also observed in a 2010 human study which indicates that "N. sativa seed supplementation during specific immunotherapy of allergic rhinitis may be considered a potential adjuvant therapy" (Işık. 2010 | see Figure 3).
  • Anti-diabetes effects: The volatile compounds in nigella sativa oil have been shown to exert potent glucose lowering effects in healthy and diabetic animals (Al-Hader. 1993). Effects that occured in the absence of changes in insulin levels and are almost unsettlingly pronounced.
    Figure 4: Reduction in fasting blood glucose in the hours after the administration of 50mg/kg volatile oil extract to normal and diabetic rodents (Al-Hader. 1993).
    For those of you who are hovering around in the netherlands of glucose levels, anyway, the 14% reduction Al-Hader et al. observed in the healthy rabbits in their 1993 could in fact be enough to induce mild hypoglycemia and side effects such as ravenous appetite, feeling cold, cold sweat, being irritable and so on - an effect that's going to be particularly pronounced, because blacksee will at the same time inhibit the production of glucose in the liver that would otherwise compensate the drop in blood glucose (Al-Awadi. 1991).

    With comparatively lower doses of only 5ml of nigella sativa oil, Mohtashami et al. have recently demonstrated that the beneficial effects on blood glucose are not rodent specific.

    Figure 5: Blackseed consumed in 2x2.5ml servings everydy improves blood glucose management in healthy humans, too (Mohtashami. 2011)
    In their randomized clinical trial with 70 healthy subjects who received either 2.5 ml Black seed oil or a similarly looking mineral oil two times a day, the scientists observed achieved less pronounced, but still significant reductions in fasting blood glucose and the long(er)-term glucose marker HbA1c within only two months.

    In view of the comparatively small reductions in blood sugar (see Figure 5), it's also not surprisng that the only side effect was an occasional case of transient nausea. Notable changes in liver enzyme and kidney functional adverse effects, on the other hand, were not observed..

    Similar results have been reported for subjects with diabetes (Najmi. 2008), intact and diabetic rats (Hawsawi. 2001; Houcher. 2007) and in several cell models, like muscle cells, where it increases AMPK and GLUT4 expression (Benhaddou-Andaloussi. 2011) or the Langerhans cells (Rchid. 2004) of the pancreas of which Fararh et al. (2002) were able to show that they can partly recover their ability to release insulin in a rodent model of diabetes, when nigella sativa is administered in conjunction with nicotinic acid.
  • Cardiovascular effects - The results of a 2014 study by Mohammad et al. indicate that "[t]he use of N. sativa as an alternative therapy for hypercholesterolemia could have profound impact on the management of CVD among menopausal women especially in countries where it is readily available." In the corresponding study 1g of nigella sativa powder consumed after breakfast lead to significant improvements in lipid profiles of menopausal women (decreased total cholesterol, low density lipoprotein cholesterol and triglyceride, and increased high density lipoprotein cholesterol)within 2 months. Improvements that were lost almost completely after one month without the capped Nigella sativa supplement.

    Rather ambigous - at least at first sight - are the effects of nigella sativa on the physiology of the heart, while Al-Asoom et al. (2014a) were able to show that the IFG-1 boosting effects Nigella sativa exerts on exercising rats could make it a valuable tool for the treatment of heart failure with superior advantages to exercise training alone, the same effects are often mentioned as potential unwanted side effects of Nigella sativa.
    Figure 6: In trained rats, the Nigella sativa induced boost in IGF-1 (left) promotes the exercise induced increase in heart weight (right | Al-Asoom. 2014a)
    Whether that's actually a problem is yet questionable. In view of the nature of the cardiac hypertrophy, it's rather an augmentation of the beneficial cardiac remodeling due to exercise similar to the one we call "athletes heart" than a pathological increase in the size of the heart. Whether similar effects can be observed for skeletal muscle has, at least as far as I know, yet not been tested - it's yet certainly not impossible.
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There is more, to Nigella sativa, but I am tired of listing all the references to its beneficial gastropotective effects, its ability to protect the kidneys and the liver from damage, its anti-stress and anti-anxiety effects, its beneficial effects against candida, bacterial infections and fungi, or its use as a post-coital contraceptive (acute high dose) and fertility booster (chronic low dose | Al-Sa'aidi. 2009) in females & males, respectively. If you want all the details, I suggest the review by Paarakh from 2010 or asking your local oriental medicine practitioner ;-).

The latter may also be a good idea if you want to know how much and which form of blackseed you have to take for whatever you want to achieve, 'cause unlike the traditional uses most of which are backed by scientific studies, "optimal" dosages still await investigation | Comment!
References
    • Abbas, Ayman Talatt, et al. "Effect of dexamethasone and Nigella sativa on peripheral blood eosinophil count, IgG1 and IgG2a, cytokine profiles and lung inflammation in murine model of allergic asthma." The Egyptian journal of immunology/Egyptian Association of Immunologists 12.1 (2004): 95-102.
    • Abdel-Fattah, Abdel-Fattah Mohamed, Kinzo Matsumoto, and Hiroshi Watanabe. "Antinociceptive effects of< i> Nigella sativa</i> oil and its major component, thymoquinone, in mice." European journal of pharmacology 400.1 (2000): 89-97. 
    • Al-Sa'aidi, J. A. A., A. L. D. Al-Khuzai, and N. F. H. Al-Zobaydi. "Effect of alcoholic extract of Nigella sativa on fertility in male rats." Iraq J Verterin Sci 23 (2009): 123-8.
    • Al-Asoom, L. I., et al. "Effect of Nigella sativa Supplementation to Exercise Training in a Novel Model of Physiological Cardiac Hypertrophy." Cardiovascular toxicology (2014a): 1-8. 
    • Al-Asoom, Lubna Ibrahim, et al. "Comparison of Nigella sativa-and Exercise-Induced Models of Cardiac Hypertrophy: Structural and Electrophysiological Features." Cardiovascular toxicology (2014b): 1-6.
    • Al-Awadi, Fatania, and U. Shamte. "The effect of a plants mixture extract on liver gluconeogenesis in streptozotocin induced diabetic rats." Diabetes research (Edinburgh, Scotland) 18.4 (1991): 163-168.
    • Al-Hader, Aqel, M. Aqel, and Z. Hasan. "Hypoglycemic effects of the volatile oil of Nigella sativa seeds." Pharmaceutical Biology 31.2 (1993): 96-100.
    • Ali, B. H., and Gerald Blunden. "Pharmacological and toxicological properties of Nigella sativa." Phytotherapy Research 17.4 (2003): 299-305. 
    • Ahlatci, Adem, et al. "Radiation-modifying abilities of< i> Nigella sativa</i> and Thymoquinone on radiation-induced nitrosative stress in the brain tissue." Phytomedicine 21.5 (2014): 740-744. 
    • Benhaddou-Andaloussi, Ali, et al. "The in vivo antidiabetic activity of Nigella sativa is mediated through activation of the AMPK pathway and increased muscle Glut4 content." Evidence-Based Complementary and Alternative Medicine 2011 (2011).
    • Cikman, Oztekin, et al. "Radioprotective Effects of Nigella Sativa Oil Against Oxidative Stress in Liver Tissue of Rats Exposed to Total Head Irradiation." Journal of Investigative Surgery (2014).
    • Fararh, K. M., et al. "Isulinotropic properties of< i> Nigella sativa</i> oil in Streptozotocin plus Nicotinamide diabetic hamster." Research in veterinary science 73.3 (2002): 279-282.
    • Hawsawi, Zubaida A., Basil A. Ali, and Abdullah O. Bamosa. "Effect of Nigella sativa (black seed) and thymoquinone on blood glucose in albino rats." Annals of Saudi medicine 21.3-4 (2001): 242-244. 
    • Houcher, Zahira, et al. "Effects of methanolic extract and commercial oil of Nigella sativa L. on blood glucose and antioxidant capacity in alloxan-induced diabetic rats." Pteridines 18.1 (2007): 8-18.
    • Houghton PJ, Zarka R, de las Heras B, Hoult JRS."Fixed oil of Nigella sativa and derived thymoquinone inhibit eicosanoid generation in leukocytes and membrane lipid peroxidation". Planta Med 61 (1995): 33–36.
    • Ichwan, S. J., et al. "Apoptotic Activities of Thymoquinone, an Active Ingredient of Black Seed (Nigella sativa), in Cervical Cancer Cell Lines." The Chinese journal of physiology 57.5 (2014).
    • Lautenbacher LM. "Schwarzkümmelöl." Dtsch Apoth Ztg 137 (1997): 68–69.
    • Khan, Fazal, et al. "Evaluation of the effect of Nigella sativa extract on human hepatocellular adenocarcinoma cell line (HepG2) in vitro." BMC Genomics 15.Suppl 2 (2014): P63.
    • Kundu, Juthika, et al. "Mechanistic Perspectives on Cancer Chemoprevention/Chemotherapeutic Effects of Thymoquinone." Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis (2014).
    • Mahmoud, M. R., H. S. El-Abhar, and S. Saleh. "The effect of< i> Nigella sativa</i> oil against the liver damage induced by< i> Schistosoma mansoni</i> infection in mice." Journal of ethnopharmacology 79.1 (2002): 1-11. 
    • Mohtashami, R., et al. "Blood Glucose Lowering Effects of Nigella Sativa L. Seeds Oil in Healthy Volunteers: a Randomized, Double-Blind, Placebo-Controlled Clinical Trial." Journal of Medicinal Plant 10.36 (2011): 90-94.
    • Mutabagani, A., and S. A. M. El-Mahdy. "A study of the anti-inflammatory activity of Nigella sativa L. and thymoquinone in rats." Saudi Pharmaceutical Journal 5 (1997): 110-113.
    • Nagi, Mahmoud N., et al. "Thymoquinone protects against carbon tetrachloride hetatotoxicity in mice via an antioxidant mechanism." IUBMB Life 47.1 (1999): 153-159. 
    • Najmi, Ahmad, et al. "Effect of Nigella sativa oil on various clinical and biochemical parameters of insulin resistance syndrome." International journal of diabetes in developing countries 28.1 (2008): 11.
    • Ozugurlu, F., et al. "The effect of Nigella sativa oil against experimental allergic encephalomyelitis via nitric oxide and other oxidative stress parameters." Cellular and molecular biology (Noisy-le-Grand, France) 51.3 (2005): 337-342.
    • Pace, Andrea, et al. "Neuroprotective effect of vitamin E supplementation in patients treated with cisplatin chemotherapy." Journal of Clinical Oncology 21.5 (2003): 927-931. 
    • Paarakh, Padmaa M. "Nigella sativa Linn.–A comprehensive review." Indian J Nat Prod Resour 1 (2010): 409-29.
    • Rchid, Halima, et al. "Nigella sativa seed extracts enhance glucose‐induced insulin release from rat‐isolated Langerhans islets." Fundamental & clinical pharmacology 18.5 (2004): 525-529.
    • Sindi, Abrar, and Karen Carlberg. "Thymoquinone, a component of the Middle East spicy seed Nigella sativa, decreases oxidative DNA damage in a rat model of mammary cancer (693.21)." The FASEB Journal 28.1 Supplement (2014): 693-21.
    • Tabasi, Nafise, et al. "Cytotoxic and apoptogenic properties of Nigella sativa and thymoquinone, its constituent, in human renal cell carcinoma are comparable with cisplatin." Food and Agricultural Immunology ahead-of-print (2014): 1-19.
    • Türkdoğan, M. K., et al. "The role of antioxidant vitamins (C and E), selenium and Nigella sativa in the prevention of liver fibrosis and cirrhosis in rabbits: new hopes." DTW. Deutsche tierarztliche Wochenschrift 108.2 (2001): 71-73.
    • Worthen, David R., Omar A. Ghosheh, and P. A. Crooks. "The in vitro anti-tumor activity of some crude and purified components of blackseed, Nigella sativa L." Anticancer research 18.3A (1997): 1527-1532.