Movaghati MRA, Yousefi M, Saghebi SA, Vazin MS, Iraji A, Mosavat AH. Efficacy of black seed (Nigella sativa L) on kidney stone dissolution: a randomized, double-blind, placebo-controlled clinical trial. Phytother Res. 2019;33(5):1404-1412.
To evaluate the safety and renal lith–dissolving efficacy of Nigella sativa and its effects on related urine and blood biochemical factors
Double-arm, randomized, double-blind, placebo-controlled clinical trial
The study included 60 adult men and women; 30 in the placebo arm and 30 in the treatment arm.
There were no significant differences in age between placebo (42.73 years) and treatment (41.78 years) arms. Among males, 55% were in the placebo arm and 45% in the treatment arm. Among females, 45% were in the placebo arm and 55% in the treatment arm.
Twenty to 60 years old with kidney stones larger than 5 mm confirmed by ultrasonography
Pregnancy, lactation, more severe renal disorders, or a known allergy to N sativa
Renal ultrasonography pre- and post-clinical trial, serum calcium, and urine pH
A botanist purchased N sativa seeds from a Mashhad, Iran, herbal market and then kept a voucher specimen in the Faculty of Pharmacy Herbarium, Mashhad University of Medical Sciences, Mashhad, Iran. The authors ground the seeds, passed them through a 120-mesh sieve, filled capsules with 500 mg of the ground seed, and filled placebo capsules with starch to the same size and weight as the seed capsules. They placed the capsules into placebo or treatment bottles of the same size and with the same label and shape. Dose was 500 mg BID of placebo or treatment for 10 weeks. The authors instructed both arms to consume their capsules with honey syrup; specifically, 1 tablespoon of honey in 150 cm lukewarm water.
The authors used gas chromatography to determine the N sativa ground seed essential oil constituents. They identified 31 named and 2 unknown essential oils. Free radical scavenging capacity and total phenol capacity (Folin-Ciocalteau Method) in milligrams of gallic acid per gram of black seed was 172.71 ± 4.01 mg/g. Phenolic compounds reduce renal lith deposition. The free-radical scavenging of N sativa was IC50 = 6.88 ± 0.92 mg/mL; quercetin as the control had an IC50 = 3.01 ± 1.72 µM.
Regardless of baseline lith diameter, in the placebo arm 4 patients (15.3%) completely excreted their liths, and in the treatment arm 12 patients (44.4%) completely excreted their liths (P=0.035). The relative risk (RR) of lith excretion was over two and a half times more likely to occur in the treatment arm vs. placebo arm (RR=2.88). Renal lith size reduction was significant in the treatment arm, 6.20 mm to 2.60 mm (P=0.001). Renal lith size reduction was not significant in the placebo arm, 6.41 mm to 5.53 mm (P=0.098).
The authors found that initial lith size was an important factor in stone excretion. Among liths 5.0-6.9 mm diameter, 45% were excreted and 55% decreased in size in the treatment arm, while in the placebo arm, 21% were excreted, 15% decreased in size, 52% were unchanged, and 11% increased in size. Among liths >7 mm in diameter, in the treatment arm 40% were excreted, 40% decreased in size, and 20% were unchanged, while in the placebo arm 71% were unchanged and 29% increased in size.
Serum calcium (mg/dL) increased in the treatment arm from 9.09 to 9.37 (P=0.001) and was unchanged in the placebo arm, 9.20 to 9.28 (P=0.146). Urine pH trended toward a decrease in the treatment arm, from pH 5.19 to 5.04 (P=0.46), and was unchanged in the placebo arm, 5.38 to 5.38 (P=0.317).
A physician followed participants every 2 weeks, and less than 70% consumption of capsules led to exclusion from the trial. In the treatment arm 1 male developed hydronephrosis and hypertension and was excluded, and 2 other patients were lost to follow-up and excluded. In the placebo arm 1 patient became pregnant and was excluded, and 3 other patients were lost to follow-up and excluded.
With the exception of the male who developed hydronephrosis and hypertension, N sativa was well tolerated. It significantly increased serum calcium. It was also more effective on smaller renal liths, especially those under 7 mm diameter as none of these increased in diameter and many of the smaller ones decreased in size or were completely excreted.
In a previous rat study, 250 mg/kg of N sativa (aqueous-ethanol extract of the N-butanol fraction and N-butanol phase remnant) prevented calcium oxalate renal calculi formation (induced by 1% ethylene glycol drinking water) compared to controls over 28 days.1 In this experiment, through microscopic analysis of each kidney, the authors saw multiple calcium oxalate crystals in the controls but saw none in the N sativa group.1 The authors assumed from prior studies that thymoquinone (TQ) was the active constituent preventing calcium oxalate crystal formation.1,2 The alcohol extract was more effective at calcium oxalate renal lith prevention than simple dissolution of N sativa.2 The authors also found N sativa to inhibit 5-lipoxygenase and cyclooxygenase pathways in these studies.1,2
TQ is an essential oil found in N sativa (0.4%-2.5%). Among the Lamiaceae family, TQ is found in the genera Agastache, Coridothymus, Monarda, Mosla, Origanum, Satureja, and Thymus, and in the Cupressaceae family, it is found in the Cupressus and Juniperus genera. It is primarily in the seeds of N sativa, but in the aerial portions of the other species.3 TQ has been investigated for its protective effects in asthma, hypertension, diabetes, renal disease, inflammation, analgesia, and fever, and as an antischistosomal, antifungal, antibacterial, anticancer, anticonvulsant, hepatoprotective, and neuroprotective agent.3
Chemotherapeutic agents that are nephrotoxic include cisplatin and doxorubicin, both of which can be mitigated by TQ.4 In experimental animal models of renal disease, TQ lowered the oxidative stress induced by doxorubicin.5 It suppressed doxorubicin- and cisplatin-induced nephrosis and lowered serum urea, triglycerides, total cholesterol, and lipid peroxides.5 In cisplatin-induced nephrotoxicity, TQ provided better kidney protection than vitamin E, vitamin C, selenium, curcumin, or lycopene.5 TQ also protected against CCl hepatotoxicity by lowering liver enzyme levels and increasing glutathione levels.5 TQ inhibited COX-1, COX-2, and lipoxygenase, implying it may have a potent anti-inflammatory effect.5
In rats induced into hypertension, TQ normalized creatinine and glutathione. It inhibited activation of IL-6.4 TQ improved mesenteric artery function in rats subjected to cecal ligation and puncture. In a rat rheumatoid arthritis model, TQ (2 mg/kg) plus methotrexate decreased inflammation, leukocytes, serum creatinine, and blood urea nitrogen.4 Its effects were comparable to losartan and captopril in a rat unilateral ureteral obstruction model. It was found protective in renal ischemia-reperfusion models on kidneys, lungs, and liver in rats (10 mg/kg).4 In streptozotocin-induced type 1 diabetes in rats, TQ reduced NF-KB activation by angiotensin II; and decreased capsular thickening, changes in basement membrane, tubular dilatation, nitric oxide levels, and overexpression of TGF-beta-1, VEGF-A, and collagen IV. TQ can also mitigate the negative renal effects of diesel exhaust particle, morphine, gentamicin, methotrexate, acetaminophen, cyclosporine A, lead, arsenic, cadmium, and mercury chloride.4 The maximum tolerated intraperitoneal dose in rats is 15-22 mg/kg, while the maximum oral dose is 250 mg/kg.4 Its oral half-life is 274.61 minutes, and its intravenous half-life is 63.43 minutes.4
Other benefits of TQ include antimicrobial activity against multiple bacteria and biofilms, as well as anti-fungal, anti-Entamoeba histolytica, anti-Giardia lamblia, and anti-H2N2 activity.4 It can also protect against ethanol-induced gastrointestinal damage.4
In human trials TQ has been used for type 2 diabetes (0.7-3.0 g seed/day), reducing insulin, fasting blood glucose, and HbA1c; in epileptic children (40 mg/kg/8 h), reducing seizure frequency; in elderly adults (500 mg BID), enhancing cognition, memory, and attention; in female menstrual pain (600 mg oil BID topical) to reduce mastalgia pain scores; in asthma (15 mL/kg/day oil) to reduce pulmonary reactivity; in vitiligo, topical oil BID to reduce lesion size; in hepatitis C (450 mg oil TID) to reduce viral load and improve liver function; in HIV positive patients (10 mL oil BID) to reduce viral load and elevate CD4 counts; in Helicobacter pylori infection (1-3 g powder/d) to eradicate the infection compared to triple therapy; in infertile men (2.5 mL oil BID) to enhance sperm counts, motility, and morphology; in rheumatoid arthritis (500 mg oil BID) to reduce disease symptoms; in celiac disease (450 mg oil BID) to correct refractory iron deficiency anemia; and in acute lymphocytic leukemia (80 mg/kg/day oil) after methotrexate to reduce hepatotoxicity and improve survival.6,7
Renal liths are a significant clinical problem affecting about 10%-12% of the United States population, with a recurrence rate of 50%, a decreasing time between recurrences, and a male to female ratio of 3:1.8 About 60% of liths are calcium oxalate, 20% calcium phosphate, 9%-10% uric acid, 8%-10% struvite, 0.5%-1.5% cysteine, and 0.5% other (xanthine, indinavir, triamterene, or 2,8 dihydroxyadenine).8 Renal liths increase the risk of kidney failure, urinary stasis, obstruction, pyelonephritis, and squamous cell carcinoma, especially if staghorn stones.8 Conventional treatment is corporeal shock wave lithotripsy, percutaneous nephrolithotomy, and open renal surgery, with prevention-based on thiazides, allopurinol, and potassium citrate.8 Oxalate exposure and chronic inflammation increase the risk of lith formation as they up-regulate the COX-2 enzyme that aids in binding and further inflammation, setting up a vicious cycle.8 Botanical treatments include catechin and epicatechin, Berberis vulgaris, Phyllanthus niruri, Oenothera biennis, Trigonella foenum-graecum, Tribulus terestris, Hibiscus sabdariffa, Desmodium, styracifolium, Herniaria hirsute, Asparagus racemosus, Crataeva nurvala, Alisma orientalis, and Solidago spp., with additional herbs suggested to aid in lith passage.9-11 While all of the previous botanicals have some level of positive animal data, only P niruri, H sabdariffa, and N sativa have been subjected to human clinical trials with positive results. Prevention is preferred to treatment, and adequate water, orange juice, pomegranate juice, vitamin B6, and magnesium have been shown to be effective in human trials.9
The study under review here flowed from the doctoral dissertation of the primary author at Mashhad University. The study was well written and generally easy to follow. This research group has a special interest in renal pathology and has published a number of studies on N sativa, treatment of renal liths, and diverse renal pathologies. The authors make the assumption that TQ is the active ingredient, and appear to ignore the potential for synergism among the 32 other constituents identified, or that there may be other factors to explain the beneficial effects of N sativa.
Ground N sativa seeds in capsules at 500 mg BID for 10 weeks reduced the number of renal liths, especially those under 7 mm diameter, in the treatment group compared to the placebo group. In the placebo group, significantly fewer renal liths disappeared, 52% were unchanged, and 11% increased in size, while none increased in size in the treatment arm. In the treatment arm, serum calcium increased and urine pH decreased significantly. N sativa appears to be a promising treatment for smaller renal liths, and the authors assume that TQ is the active ingredient.
- Hadjzadeh MAR, Rad AK, Rajaei Z, Tehranipour M, Monavar N. The preventive effect of N-Butanol fraction of Nigella sativa on ethylene glycol-induced kidney calculi in rats. Pharmacogn Mag. 2011;7(28):338-343.
- Zarei M, Rahmani Z. Effects of methanol extract and essential oil of Nigella sativa on ethylene glycol-induced kidney stones in rats. Avicenna J Phytomed. 2015;Supp5:152-155.
- Shaterzadeh-Yazdi H, Noorbakhsh MF, Samarghandian S, Farkhondeh T. An overview on renoprotective effects of thymoquinone. Kidney Dis (Basel). 2018;4(2):74-82.
- Goyal SN, Prajapati CP, Gore PR, et al. Therapeutic potential and pharmaceutical development thymoquinone: a multitargeted molecule of natural origin. Front Pharmacol. 2017;8:656.
- Ragheb A, Attia A, Eldin WS, Elbarbry F, Gazarin S, Shoker A. The protective effect of thymoquinone, an anti-oxidant and anti-inflammatory agent, against renal injury: a review. Saudi J Kidney Dis Transpl. 2009;20(5):741-752.
- Tavakkoli A, Mahdian V, Razavi BM, Hosseinadeh H. Review on clinical trials of black seed (Nigella sativa) and its active constituent, thymoquinone. J Pharmacopuncture. 2017;20(3):179-193.
- Kahn MA, Tania M, Fu S, Fu J. Thymoquinone, as an anticancer molecule: from basic research to clinical investigation. Oncotarget. 2017;8(31):51907-51919.
- Havatdavoudi P, Khajayi Rad A, Rajaei Z, Hadjzadeh MA. Renal injury, nephrolithiasis and Nigella sativa: a mini review. Avicenna J Phytomed. 2016;6(1):1-8.
- Winston D. Herbal and nutritional treatment of kidney stones. J American Herbalist Guild. 2012;10(2):61-71.
- Butterweck V, Kahn SR. Herbal medicines in the management of urolithiasis: alternative or complementary? Planta medica. 2009;75(10):1095-1103.
- Bahmani M, Baharvand-Ahmadi B, Tajeddini P, Rafieian-Kopaei M, Naghdi N. Identification of medicinal plants for the treatment of kidney and urinary stones. J Renal Inj Prev. 2016;5(3):129-133.