Efficacy of Black Seed (Nigella sativa) and Lemon Balm (Melissa officinalis) on Non-Alcoholic Fatty Liver Disease: A Randomized Controlled Clinical Trial


Seyed Mousal-Reza Hosseini 1 , Gholam Reza Ghayour Razmgah 2 , * , Mohsen Nematy 3 , Habibollah Esmaily 4 , Mahdi Yousefi 5 , Mohammad Kamalinejad 6 , Seyed Hamdollah Mosavat 7 , *

1 Department of Gastroenterology and Hepatology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, IR Iran

2 Faculty of Iranian Traditional Medicine and Complementary Medicine, Mashhad University Medical of Sciences, Mashhad, IR Iran

3 Department of Nutrition, School of Medicine, Biochemistry and Nutrition, Endoscopic & Minimally Invasive Surgery and Cancer Research Centers, Mashhad University of Medical Sciences, Mashad, IR Iran

4 Health Sciences Research Center, Department of Biostatistics and Epidemiology, School of Health, Mashhad University of Medical Sciences, Mashhad, IR Iran

5 Department of Persian Medicine, School of Persian and Complementary Medicine, Mashhad University of Medical Sciences, Mashhad, IR Iran

6 School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran

7 Research Centre for Traditional Medicine and History of Medicine, Shiraz University of Medical Sciences, Shiraz, IR Iran

Corresponding Authors:

How to Cite: Hosseini S M, Ghayour Razmgah G R, Nematy M, Esmaily H, Yousefi M, et al. Efficacy of Black Seed (Nigella sativa) and Lemon Balm (Melissa officinalis) on Non-Alcoholic Fatty Liver Disease: A Randomized Controlled Clinical Trial, Iran Red Crescent Med J. 2018 ; 20(3):e59183. doi: 10.5812/ircmj.59183.


Iranian Red Crescent Medical Journal: 20 (3); e59183
Published Online: March 17, 2018
Article Type: Research Article
Received: August 9, 2017
Revised: October 11, 2017
Accepted: February 14, 2018




Background: There are several therapeutic strategies available from the viewpoint of Traditional Persian Medicine (TPM) to treat hepatic diseases.

Objectives: This study aimed at assessing the efficacy and safety of Nigella sativa and Melissa officinalis in patients with Non-Alcoholic Fatty Liver Disease (NAFLD).

Methods: From November 2014 to May 2016, in an open-label, simple-blocked, randomized controlled clinical trial, the researchers evaluated the efficacy of Nigella sativa and Melissa officinalis compared with Orlistat capsule on the grade of fatty liver and the serum levels of Aspartate Transaminase (AST) and Alanine Transaminase (ALT) in 50 patients with NAFLD in Iran.

Results: Regarding within-group changes, a significant decrease was observed in the serum level of AST, ALT, body mass index, and grade of fatty liver in both groups after the intervention compared with baseline (P < 0.001). Repeated measures logistic regression analysis showed that there was a more significant reduction in the grade of fatty liver over the study period in the intervention group compared with the control group (0.58 ± 0.50 versus 1.51 ± 0.54, P < 0.001).

Conclusion: Traditional Persian Medicine-based preparations of Nigella sativa and Melissa officinalis could reduce body weight and liver enzymes and improves the grade of fatty liver in Non-Alcoholic Fatty Liver Disease.


Disease Fatty Liver Lemon Balm Melissa officinalis Medicine Nigella sativa Non-Alcoholic Traditional

Copyright © 2018, Iranian Red Crescent Medical Journal. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited

1. Background

Non-Alcoholic Fatty Liver Disease (NAFLD) is a chronic disease that is predicted to become one of the main leading causes of end-stage liver disease around the world (1, 2).

Since the pathogenesis of NAFLD remains unknown in addition to the fact that NAFLD often has an association with other diseases, such as obesity, hypertension, dyslipidemia, and diabetes, the management of this condition is empirical (3). Modification of lifestyle in conjunction with medical therapy has been recommended for the treatment of NAFLD (4-6). Avoiding heavy alcohol consumption, regular exercise, and weight loss are the most important lifestyle modifications for these patients (7, 8). It is important to note that current treatments for NAFLD are inadequate and sometimes associated with side effects.

Over the past decades, there has been increasing interest in the use of complementary and alternative medicine for the treatment of chronic diseases, such as fatty liver (9-12). Traditional Persian Medicine (TPM), as an alternative medical system, has been practiced among Iranian people since ancient times (13, 14). There are several therapeutic strategies available from the viewpoint of TPM to treat hepatic diseases, ranging from lifestyle modification to herbal therapy (15-18). Black seed or Nigella sativa and lemon balm or Melissa officinalis are amongst hepatotonic plants that have long been used in TPM to treat overweightness and gastrointestinal disorders. Moreover, several preclinical and clinical studies have shown beneficial effects of these herbs in the treatment of a wide range of clinical settings, such as fatty liver, hyperlipidemia, hypertension, obesity, and diabetes mellitus (19-26). Experimental studies have shown that Nigella sativa could protect the liver against hepatic ischemia-reperfusion injury. Also, the protective role of Nigella sativa by a decrease in protein oxidation and depleted anti-oxidants rejuvenation of cellular fraction has been investigated. In another animal study, Nigella sativa significantly reduced the elevated levels of serum enzymes as well as hepatic malondialdehyde content and significantly increased hepatic non-protein sulfhydryl. Moreover, Nigella sativa contributes to inhibition of the enzymes present in the neoglucogenesis pathway in the liver (27). Previous studies on Melissa officinalis demonstrated that Melissa officinalis reduces high fat diet-induced visceral adipose tissue angiogenesis, visceral obesity, and NAFLD in obese female ovariectomized mice (28). Significant effects of Melissa officinalis on controlling blood sugar level and serum lipid profiles that attribute to the antioxidant benefits of flavonoids have been investigated as well (29).

Regarding the traditional use of Nigella sativa and Melissa officinalis in addition to their known beneficial effects in recent studies, the current researchers decided to design a randomized, controlled clinical trial to evaluate the efficacy of these herbs on the levels of liver enzymes and the grade of fatty liver in patients with Non-Alcoholic Fatty Liver Disease.

2. Materials and Methods

2.1. Trial Design

The researchers designed a randomized, double arm, open label, active-controlled clinical trial. In this trial, the effect of TPM-based diet and herbal formulation of Nigella sativa and Melissa officinalis on the grade of fatty liver and the levels of liver enzymes in patients with NAFLD was evaluated. No changes occurred in the methods after the trial commencement.

2.2. Participants

Inclusion criteria for participants enrolled in this study were age of 20 to 60 years, the presence of NAFLD (grade 1 to 3) diagnosed by ultrasound imaging, and body mass index greater than 27 kg/m2. This study was carried out in the nutrition clinic of Ghaem Hospital, a governmental, general, and referral hospital with 924 beds and more than ten wards. This clinic was affiliated to Mashhad University of Medical Sciences, Mashhad, Iran, from November 2014 to May 2016. All participants signed an informed consent form.

Exclusion criteria were affliction with diabetes, hypertension, cardiovascular diseases, familial hyperlipidemia, breastfeeding, pregnancy, drug addiction, alcohol consumption, active or previous infection with hepatitis B or C, acute liver disease, renal stones, gallstones, major surgery during the last 6 months, any surgery on the liver and gallbladder or general anesthesia drugs during the study, rapid weight loss during the last 3 months for any reason, patients undergoing special diet or exercise for weight loss or gain, and losing weight.

2.3. Intervention

After a diagnosis of fatty liver by a radiologist via sonographic assessment and confirmation of the diagnosis by a gastroenterologist, eligible patients were divided into 2-groups. Patients were randomly assigned to receive either a 3-month TPM based diet plus Hepatomelis capsules (10 mg twice per day) as the intervention group, or the low-fat low-calorie diet plus Orlistat capsules (500 mg twice per day) as the control group. Participants in the intervention group received TPM-based dietary commands by a written list of hot- and cold-natured foods and related recipes for a period of 3 months. To better understand the concept of hot- and cold-natured foods, reference could be made to previous studies (13, 30-32). Those in the control group received a low-fat and low-calorie diet for 3 months. Controls were placed on minus 500 kcal per day deficit on daily energy needs. In this diet, participants received 60% carbohydrate, 20% protein, and 20% fat. The participants were prevented from weight change by out-of-the-protocol-study diet and physical activity during the trial period. Consumption of less than 70% of the drugs during the trial was considered as drug intolerance, and the patient was excluded from the trial.

2.4. Preparation of Drugs

Hepatomelis is a type of herbal tea consisting of Nigella sativa and Melissa officinalis. The intact seeds of Nigella sativa and dry leaf of Melissa officinalis were purchased from a herbal market in Tehran (Iran) and was authenticated by a botanist (Voucher number: 8029 and 8028 respectively) and kept at the Herbarium of the Faculty of Pharmacy, Shahid Beheshti University of Medicinal Sciences, Tehran, Iran. Five grams of the intact seeds of Nigella sativa was added to 5 g of the coarse milled powder of dry leaf of the Melissa officinalis and filled in a tea bag, weighing 10 g. All patients were instructed to infuse each tea bag in 250 ml of boiled water for 10 minutes and drink according to their assigned dose.

Orlistat (Venustat, anti-obesity agent, capsule, 120 mL, Aburaihan Pharmaceutical Co) was prescribed as a routine drug for the treatment of fatty liver and was used in this study for weight loss.

2.5. Outcome Measures

The primary outcome measure in this trial was changes in the level of liver enzymes: Serum Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST). Blood samples were taken after 12 to 14 hours of overnight fasting at the baseline, sixth week, and 3 months after the intervention in 2 groups by using the International Federation of Clinical Chemistry (IFCC) approved method.

Secondary outcome measures were changes in the grade of fatty liver (fatty tissue infiltration in the liver by using ultrasound imaging) and changes in the patients’ body mass index. The Sonographic assessment was done with the device model Siemens 40 with the Acuson 15 L8 transducer after 8 hours of fasting by a radiologist. Any observed adverse event was also considered as the secondary outcome. No changes were made to trial outcomes after the trial commenced.

2.6. Sample Size

The sample size was calculated as 25 patients in each group with a total of 50 patients based on the difference in mean enzyme level of ALT obtained from previous studies, and by taking in account 2-sided significance level of 0.05, and a power of 80% (33, 34).

2.7. Safety Assessment

In order to detect possible patient complaints, all patients were followed by physicians every 2 weeks. Moreover, weight and blood pressure measurements were also carried out by the mentioned physicians.

2.8. Randomization

Fifty eligible patients were randomized to 2 parallel groups. A statistician generated a randomized list by using NCSS (statistical software) with the simple block randomization method. Then, the eligible patients were assigned to 2 groups by the secretary of the clinic, according to the randomized list. Only the statisticians were blind to the allocation of the patients.

2.9. Ethical Issues

The trial was in compliance with the Declaration of Helsinki (1989 revision), and also was reviewed, approved, and monitored by the Ethics committee of Mashhad University of Medical Sciences. The trial was registered by the Iranian Registry of Clinical Trials with the following code: IRCT2014081518807N1. All the participants signed an informed consent form prior to enrollment in the study.

2.10. Statistical Methods

All data were analyzed using SPSS statistics for Windows, version 15.0 (SPSS Inc., Chicago, IL., USA). All data were described by mean ± standard deviation (35) or number (percentage). Chi-square and Mann–Whitney U tests were used for statistical comparison of baseline characteristics. Repeated measurement Analysis of Variance (ANOVA) was used to determine changes in outcomes between the two groups of the study. P-values of less than 0.05 were considered significant.

3. Results

From November 2014 to May 2016, 78 volunteers were assessed for eligibility. Fifty patients, who met the inclusion criteria and agreed to participate in the study, were divided to 2 groups. Twenty-five patients were assigned to the intervention group and 25 patients to the control group. Figure 1 is a flowchart of the groups' distribution, recruitment, intervention, follow up, and analysis.

Flow Diagram of the Groups’ Allocation, Enrolment, Intervention, Follow-up, and the Analysis in Both Groups of the Study
Figure 1. Flow Diagram of the Groups’ Allocation, Enrolment, Intervention, Follow-up, and the Analysis in Both Groups of the Study

Baseline demographic data of the study groups (age, gender, marital status body mass index, the serum level of AST and ALT, and sonographic grade of fatty liver) are shown in Table 1. The mean age of participants was 46.33 (± 10.82) and 40.35 (± 11.96) years in the intervention and control groups, respectively. As shown in Table 1, no significant differences were observed in baseline demographic data between the 2 groups of the study, except a significant difference that was observed between the study groups in terms of baseline ALT (39.46 ± 27.26 versus 60.30 ± 48.86, P value = 0.021) and Fasting Blood Sugar (FBS) (102.52 ± 22.13 versus 92.62 ± 9.77, P value = 0.052).

Table 1. Baseline Demographic Data and Clinical Features of the Trial Participants
Basic CharacteristicsIntervention Group (n = 24)Control Group (n = 23)P-Value
Mean age, y46.33 ± 10.8240.35 ± 11.960.86
Sex, N.%0.557
Male12 (50)11 (47.82)
Female12 (50)12 (52.18)
Marital status, %0.234
Married0 (0)2 (8.6)
Married24 (100)21 (91.4)
AST33.92 ± 14.1847.26 ± 33.580.187
ALT39.46 ± 27.2660.30 ± 48.860.021
Height, cm166.17±6.90167.65±10.470.567
Weight, kg81.91±7.1781.72±10.400.942
BMI, kg/m229.60±0.4728.97±0.880.063
FBS, mg/dl92.62±9.77102.52±22.130.052
Grade of fatty liver0.814
Grade 16 (25.00)4 (17.40)
Grade 215 (62.50)16 (69.56)
Grade 33 (12.50)3 (13.04)

Regarding within-group changes, a significant decrease was observed in the the serum level of AST and ALT, body mass index, and grade of fatty acid in both groups after the intervention compared to baseline (Table 2). The trend of changes in outcome measures is shown in Figure 2.

Repeated measures logistic regression analysis showed that there was a more significant reduction in the grade of fatty liver over the study period in the intervention group compared with the control group (P < 0.001). Details of the grade of fatty liver change are shown in Table 3.

Table 2. Mean Values (Mean ± SD) for Aspartate Aminotransferase (AST), Alanine Aminotransaminase (ALT), Body Mass Index (BMI) and Grade of Fatty Liver in the Intervention and Control Groups Before and After the Intervention
InterventionControlP Value
AST, units per liter
Baseline33.92 ± 14.1847.26 ± 33.580.187
6 weeks26.96 ± 7.2232.35 ± 11.040.056
12 weeks24.71 ± 6.6427.91 ± 7.040.116
P value< 0.001< 0.001
ALT, units per liter
Baseline39.46 ± 27.2660.30 ± 48.860.021
6 weeks29.29 ± 11.3640.4 ± 21.860.130
12 weeks24.63 ± 8.4627.35 ± 7.770.257
P value< 0.006< 0.001
BMI, kg/m2
Baseline29.60 ± 0.4728.97 ± 0.880.063
6 weeks28.44 ± 0.6928.07 ± 0.880.112
12 weeks27.60 ± 0.9327.36 ± 0.850.365
P value< 0.001< 0.001
Grade of fatty liver
Baseline1.88 ± 0.611.96 ± 0.560.814
6 weeks1.21 ± 0.411.83 ± 0.49< 0.0001
12 weeks0.58 ± 0.501.51 ± 0.54< 0.0001
P value< 0.001< 0.001
Table 3. Frequency Distribution of the Grade of Fatty Liver in the Intervention and Control Groups During the Study Period
Time/ Grade of Fatty LiverIntervention Group N (%)Control Group N (%)
Grade 16 (25)4 (17.4)
Grade 215 (62.5)16 (69.6)
Grade 33 (12.5)3 (13)
6 weeks
Grade 119 (79.2)5 (21.7)
Grade 25 (20.8)17 (73.9)
Grade 30 (0)1 (4.4)
12 weeks
Grade 010 (41.7)0 (0)
Grade 114 (58.3)17 (73.9)
Grade 20 (0)6 (26.1)
Comparison of Aspartate Aminotransferase, Alanine Aminotransaminase, Body Mass Index and Grade of Fatty Liver Before and After Three Months of Intervention in Both Study Groups
Figure 2. Comparison of Aspartate Aminotransferase, Alanine Aminotransaminase, Body Mass Index and Grade of Fatty Liver Before and After Three Months of Intervention in Both Study Groups

4. Discussion

Safety and efficacy of Nigella sativa and Melissa officinalis on NAFLD was evaluated in this study via an open-label randomized controlled clinical trial. Although all of the outcome measures of the study (serum level of AST and ALT, and BMI) improved in both groups, the Nigella sativa and Melissa officinalis had better effects on reducing sonographic grade of fatty liver in patients with NAFLD, compared with orlistat.

Currently, weight loss and calorie restriction is known as the first effective treatment for NAFLD (36). Weight loss causes reduction of hepatic fat content, consequently leading to improved liver function (37). Insulin-sensitizing agents, such as metformin and thiazolidinediones, lipid lowering drugs, such as orlistat and statins, hepato-protective agents, such as ursodeoxycholic acid, and antioxidants, such as vitamin C and E, are medications that have been used for NAFLD (38, 39).

There are several herbal remedies that reveal probable advantage for management of NAFLD. The most commonly used herbs were Cassia obtusifolia, Crataegus pinnatifida, Alisma orientalis, Salvia miltiorrhiza, Bupleurum chinense, Rheum p almatum, and Astragalus membranaceous (40). Most of these herbs are used in Traditional Chinese Medicine (TCM) to manage NAFLD by nourish Qi, strengthen the liver and spleen, and clear heat or discharge phlegm based on TCM theories (40). Moreover, the efficacy of some traditional Persian medicinal herbs on hepatic disorders,, such as NAFLD has been evaluated in previous animal and clinical studies. The most commonly used herbs were Rosa damascena Mill, Chlorella vulgaris, Camelia sinensis, Glycyrrhiza glabra L., Phyllanthus urinaria, cuminum cyminum L., Berberis Vulgaris L., and Cinnamom umzeylanicum (41-47). According to TPM, changes in the liver temperament toward cold temperament and decrease in hepatic strength could result in chronic diseases, such as what is now known as NAFLD in current medicine (48). Hence, hepatotonic and warm temperament herbs are usually used for management of NAFLD (49).

The black seed, as a dry and warm temperament herb, is used in TPM for the treatment of NAFLD. A previous study showed that Nigella sativa in combination with Urtica dioica L decreases lipid per-oxidation and liver enzymes, and increases anti-oxidant defense system activity in carbon tetrachloride-treated rats (50). Also, Nigella sativa oil has a favorable effect on reducing serum total cholesterol, low density lipoprotein and triglycerides, and elevating serum high density lipoprotein level in the carbon tetrachloride-treated rats (51). In experimentally-induced diabetic rabbits, Nigella sativa caused prevention of lipid peroxidation, increased anti-oxidant defense system activity and also prevented liver damage (52). Sahar et al. in their animal study revealed that the crude oil of Nigella sativa seed may potentially be used as a dietary supplement for prevention of inflammatory fatty liver. Thymoquinone, as an active constituent of Nigella sativa was reported to prevent oxidative stress injury in hepatocytes (22). Vedanarayanan et al., in their study showed that extract of Nigella sativa could reduce lipid profile and liver enzymes of rats fed with high-fat diets (53).

The lemon balm, as another dry and warm temperament herb, is used in TPM for the treatment of liver diseases. A previous study showed that the administration of Melissa officinalis extract reduced total cholesterol, total lipid, ALT and AST levels in the serum, and lipid peroxidation levels in the liver tissue, and increased the glutathione levels in the liver of hyperlipidemic rats (20). Moreover, Melissa officinalis essential oil reduces the plasma triglycerides in human apolipoprotein E2 transgenic mice by inhibiting sterol regulatory element-binding protein-1c-dependent fatty acid synthesis (54). Chung et al. in their animal study revealed that Melissa officinalis was an efficient hypoglycaemic agent, probably due to enhanced glucose uptake and metabolism in the liver and adipose tissue, and the inhibition of gluconeogenesis in the liver (55). Zarei et al. in 2014 suggested that Melissa officinalis extract exerted a hypolipidemic effect similar to atorvastatin and showed a protective effect on the liver of hyperlipidemic rats (23). They continued their research in 2016 and showed that the extract of Melissa officinalis reduced levels of liver enzymes, particularly alkaline phosphatase and gamma-glutamyl transferase, and it was effective in improving liver function (56). Jeongjun Kim et al. revealed that Melissa officinalis attenuates NAFLD by reducing visceral adipose tissue mass and regulates visceral adipose tissue dysfunction, leading to attenuation of obesity-induced NAFLD and NASH (57).

To the best of the authors’ knowledge, this was the first clinical trial that evaluated safety and efficacy of the Nigella sativa and Melissa officinalis, on NAFLD. However, the current study also had some limitations. Short time duration of the study, lack of a placebo group, lack of more accurate objective indices like liver biopsy for the assessment of patients' grade of fatty liver and the small sample size, were the main limitations of this study. In addition, this study was an open-label study that may possibly have some bias.

4.1. Conclusion

This randomized open-label controlled clinical trial demonstrated that TPM-based preparation of black seed and lemon balm could reduce body weight and liver enzymes and improve grade of fatty liver in NAFLD. However, larger-scale qualified methodological trials with longer duration of the intervention are needed to replicate and expand preliminary findings in this trial.



  • 1.

    Seth A, Balakrishnan M. Nonalcoholic Fatty Liver Disease. Managing Gastrointestinal Complications of Diabetes. Springer; 2017.

  • 2.

    Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, Younossi ZM, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015;148(3):547-55. doi: 10.1053/j.gastro.2014.11.039. [PubMed: 25461851].

  • 3.

    Angulo P, Lindor KD. Treatment of nonalcoholic fatty liver: present and emerging therapies. Semin Liver Dis. 2001;21(1):81-8. [PubMed: 11296699].

  • 4.

    Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51(1):121-9. doi: 10.1002/hep.23276. [PubMed: 19827166].

  • 5.

    Keating SE, Hackett DA, George J, Johnson NA. Exercise and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol. 2012;57(1):157-66. doi: 10.1016/j.jhep.2012.02.023. [PubMed: 22414768].

  • 6.

    Mummadi RR, Kasturi KS, Chennareddygari S, Sood GK. Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2008;6(12):1396-402. doi: 10.1016/j.cgh.2008.08.012. [PubMed: 18986848].

  • 7.

    Sheth SG, Chopra S, Lindor KD. Natural history and management of nonalcoholic fatty liver disease in adults. Natur History. 1914;(9):10.

  • 8.

    Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH. Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol. 2009;51(2):371-9. doi: 10.1016/j.jhep.2009.03.019. [PubMed: 19501928].

  • 9.

    Hashempur MH, Heydari M, Mosavat SH, Heydari ST, Shams M. Complementary and alternative medicine use in Iranian patients with diabetes mellitus. J Integrat Med. 2015;13(5):319-25.

  • 10.

    Samani NB, Jokar A, Soveid M, Heydari M, Mosavat SH. Efficacy of the Hydroalcoholic Extract of Tribulus terrestris on the Serum Glucose and Lipid Profile of Women With Diabetes Mellitus: A Double-Blind Randomized Placebo-Controlled Clinical Trial. J Evid Based Complementary Altern Med. 2016;21(4):NP91-7. doi: 10.1177/2156587216650775. [PubMed: 27255456].

  • 11.

    Cicero AF, De Sando V, Izzo R, Vasta A, Trimarco A, Borghi C. Effect of a combined nutraceutical containing Orthosiphon stamineus effect on blood pressure and metabolic syndrome components in hypertensive dyslipidaemic patients: a randomized clinical trial. Complement Ther Clin Pract. 2012;18(3):190-4. doi: 10.1016/j.ctcp.2012.02.002. [PubMed: 22789797].

  • 12.

    Hosseini B, Saedisomeolia A, Wood LG, Yaseri M, Tavasoli S. Effects of pomegranate extract supplementation on inflammation in overweight and obese individuals: A randomized controlled clinical trial. Complement Ther Clin Pract. 2016;22:44-50. doi: 10.1016/j.ctcp.2015.12.003. [PubMed: 26850805].

  • 13.

    Rezaeizadeh H, Alizadeh M, Naseri M, Ardakani MS. The Traditional Iranian Medicine Point of View on Health. Iranian J Publ Health. 2009;38(1):169-72.

  • 14.

    Shoara R, Hashempur MH, Ashraf A, Salehi A, Dehshahri S, Habibagahi Z. Efficacy and safety of topical Matricaria chamomilla L. (chamomile) oil for knee osteoarthritis: A randomized controlled clinical trial. Complement Ther Clin Pract. 2015;21(3):181-7. doi: 10.1016/j.ctcp.2015.06.003. [PubMed: 26256137].

  • 15.

    Asadi-Samani M, Kafash-Farkhad N, Azimi N, Fasihi A, Alinia-Ahandani E, Rafieian-Kopaei M. Medicinal plants with hepatoprotective activity in Iranian folk medicine. Asia Pacific J Tropic Biomed. 2015;5(2):146-57.

  • 16.

    Choopani R, Emtiazy M. The concept of lifestyle factors, based on the teaching of avicenna (ibn sina). Int J Prevent Med. 2015;6.

  • 17.

    Movahhed M, Mosaddegh M, Farsani GM, Abolhasani MH. History of fatty liver in Medieval Iranian Medicine. Health Med. 2013;7:786-92.

  • 18.

    Zohalinezhad ME, Imanieh MH, Samani SM, Mohagheghzadeh A, Dehghani SM, Haghighat M, et al. Effects of Quince syrup on clinical symptoms of children with symptomatic gastroesophageal reflux disease: A double-blind randomized controlled clinical trial. Complement Ther Clin Pract. 2015;21(4):268-76. doi: 10.1016/j.ctcp.2015.09.005. [PubMed: 26573454].

  • 19.

    Salem ML. Immunomodulatory and therapeutic properties of the Nigella sativa L. seed. Int Immunopharmacol. 2005;5(13-14):1749-70. doi: 10.1016/j.intimp.2005.06.008. [PubMed: 16275613].

  • 20.

    Bolkent S, Yanardag R, Karabulut-Bulan O, Yesilyaprak B. Protective role of Melissa officinalis L. extract on liver of hyperlipidemic rats: a morphological and biochemical study. J Ethnopharmacol. 2005;99(3):391-8. doi: 10.1016/j.jep.2005.02.038. [PubMed: 15946812].

  • 21.

    Lee J, Chae K, Ha J, Park BY, Lee HS, Jeong S, et al. Regulation of obesity and lipid disorders by herbal extracts from Morus alba, Melissa officinalis, and Artemisia capillaris in high-fat diet-induced obese mice. J Ethnopharmacol. 2008;115(2):263-70. doi: 10.1016/j.jep.2007.09.029. [PubMed: 18023310].

  • 22.

    Al‐Okbi SY, Mohamed DA, Hamed TE, Edris AE. Potential protective effect of Nigella sativa crude oils towards fatty liver in rats. Europ J Lipid Sci Technol. 2013;115(7):774-82.

  • 23.

    Zarei A, Changizi Ashtiyani S, Taheri S, Rasekh F. Comparison between effects of different doses of Melissa officinalis and atorvastatin on the activity of liver enzymes in hypercholesterolemia rats. Avicenna J Phytomed. 2014;4(1):15-23. [PubMed: 25050297].

  • 24.

    Fallah Huseini H, Amini M, Mohtashami R, Ghamarchehre ME, Sadeqhi Z, Kianbakht S, et al. Blood pressure lowering effect of Nigella sativa L. seed oil in healthy volunteers: a randomized, double-blind, placebo-controlled clinical trial. Phytother Res. 2013;27(12):1849-53. doi: 10.1002/ptr.4944. [PubMed: 23436437].

  • 25.

    Bamosa AO, Kaatabi H, Lebdaa FM, Elq AM, Al-Sultanb A. Effect of Nigella sativa seeds on the glycemic control of patients with type 2 diabetes mellitus. Indian J Physiol Pharmacol. 2010;54(4):344-54. [PubMed: 21675032].

  • 26.

    Sabzghabaee AM, Dianatkhah M, Sarrafzadegan N, Asgary S, Ghannadi A. Clinical evaluation of Nigella sativa seeds for the treatment of hyperlipidemia: a randomized, placebo controlled clinical trial. Med Archiv (Sarajevo, Bosnia Herzegovina). 2012;66(3):198-200.

  • 27.

    Kooti W, Hasanzadeh-Noohi Z, Sharafi-Ahvazi N, Asadi-Samani M, Ashtary-Larky D. Phytochemistry, pharmacology, and therapeutic uses of black seed (Nigella sativa). Chin J Natur Med. 2016;14(10):732-45.

  • 28.

    Kim J, Lee H, Lim J, Lee H, Yoon S, Shin SS, et al. The lemon balm extract ALS-L1023 inhibits obesity and nonalcoholic fatty liver disease in female ovariectomized mice. Food Chem Toxicol. 2017;106(Pt A):292-305. doi: 10.1016/j.fct.2017.05.059. [PubMed: 28571771].

  • 29.

    Khodsooz S, Moshtaghian J, Eivani M. Antihyperglycemic and antihyperlipidemic effects of hydroalcoholic extract of Melissa officinalis (Lemon Balm) in alloxan-induced diabetic rats. Physiol Pharmacol. 2016;20(1):24-30.

  • 30.

    Farsani GM, Movahhed M, Motlagh AD, Hosseini S, Yunesian M, Farsani TM. Is the Iranian Traditional Medicine warm and cold temperament related to Basal Metabolic Rate and activity of the sympathetic-parasympathetic system? Stud Protocol J Diabet Metabol Disorder. 2014;13(1):74.

  • 31.

    Parvinroo S, Zahediasl S, Sabetkasaei M, Kamalinejad M, Naghibi F. The effects of selected hot and cold temperament herbs based on Iranian traditional medicine on some metabolic parameters in normal rats. Iran J Pharm Res. 2014;13(Suppl):177-84. [PubMed: 24711844].

  • 32.

    Shahabi S, Hassan ZM, Mahdavi M, Dezfouli M, Rahvar MT, Naseri M, et al. Hot and Cold natures and some parameters of neuroendocrine and immune systems in traditional Iranian medicine: a preliminary study. J Altern Complement Med. 2008;14(2):147-56. doi: 10.1089/acm.2007.0693. [PubMed: 18307392].

  • 33.

    Yamamoto M, Iwasa M, Iwata K, Kaito M, Sugimoto R, Urawa N, et al. Restriction of dietary calories, fat and iron improves non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2007;22(4):498-503. doi: 10.1111/j.1440-1746.2006.04548.x. [PubMed: 17376040].

  • 34.

    Tendler D, Lin S, Yancy WJ, Mavropoulos J, Sylvestre P, Rockey DC, et al. The effect of a low-carbohydrate, ketogenic diet on nonalcoholic fatty liver disease: a pilot study. Dig Dis Sci. 2007;52(2):589-93. doi: 10.1007/s10620-006-9433-5. [PubMed: 17219068].

  • 35.

    Bhalerao M, Bolshete P, Swar B, Bangera T, Kolhe V, Tambe M. Use of and satisfaction with complementary and alternative medicine in four chronic diseases: A cross-sectional study from India. Natl Med J India. 2013;26(75):8.

  • 36.

    Ahmed MH, Byrne CD. Current treatment of non-alcoholic fatty liver disease. Diabetes Obes Metab. 2009;11(3):188-95. doi: 10.1111/j.1463-1326.2008.00926.x. [PubMed: 18564173].

  • 37.

    Ueno T, Sugawara H, Sujaku K, Hashimoto O, Tsuji R, Tamaki S. Therapeutic effects of restricted diet and exercise in obese patients with fatty liver. J Hepatol. 1997;27(1):103-7.

  • 38.

    Neuschwander-Tetri BA. Non-alcoholic fatty liver disease. BMC Med. 2017;15(1):45. doi: 10.1186/s12916-017-0806-8. [PubMed: 28241825].

  • 39.

    Banini BA, Sanyal AJ. Nonalcoholic Fatty Liver Disease: Epidemiology, Pathogenesis, Natural History, Diagnosis, and Current Treatment Options. Clin Med Insights Ther. 2016;8:75-84. [PubMed: 28670148].

  • 40.

    Liu ZL, Xie LZ, Zhu J, Li GQ, Grant SJ, Liu JP. Herbal medicines for fatty liver diseases. Cochrane Database Syst Rev. 2013;(8). CD009059. doi: 10.1002/14651858.CD009059.pub2. [PubMed: 23975682].

  • 41.

    Davoodi I, Rahimi R, Abdollahi M, Farzaei F, Farzaei MH, Memariani Z, et al. Promising effect of Rosa damascena extract on high-fat diet-induced nonalcoholic fatty liver. J Tradit Complement Med. 2017;7(4):508-14. doi: 10.1016/j.jtcme.2017.01.008. [PubMed: 29034200].

  • 42.

    Asadollahpoor A, Abdollahi M, Rahimi R. Pimpinella anisum L. fruit: Chemical composition and effect on rat model of nonalcoholic fatty liver disease. J Res Med Sci. 2017;21(12).

  • 43.

    Moradi MT, Asadi-Samani M, Bahmani M, Shahrani M. Medicinal plants used for liver disorders based on the Ethnobotanical documents of Iran: A Review. Drug. 2016;26:33.

  • 44.

    Rahmani S, Asgary S, Askari G, Keshvari M, Hatamipour M, Feizi A, et al. Treatment of Non-alcoholic Fatty Liver Disease with Curcumin: A Randomized Placebo-controlled Trial. Phytother Res. 2016;30(9):1540-8. doi: 10.1002/ptr.5659. [PubMed: 27270872].

  • 45.

    Mirhosseini M. A Review on the Most Important Medicinal Herbs Native to Iran with Anti-Acetaminophen Toxicity. J Global Pharma Technol. 2017:12-6.

  • 46.

    Nikkhajoei M, Choopani R, Tansaz M, Heydarirad G, Hashem-Dabaghian F, Sahranavard S. Herbal Medicines Used in Treatment of Nonalcoholic Fatty Liver Disease: A Mini-Review. Galen Med J. 2016;5(3):107-13.

  • 47.

    Panahi Y, Kianpour P, Mohtashami R, Jafari R, Simental-Mendia LE, Sahebkar A. Curcumin Lowers Serum Lipids and Uric Acid in Subjects With Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial. J Cardiovasc Pharmacol. 2016;68(3):223-9. doi: 10.1097/FJC.0000000000000406. [PubMed: 27124606].

  • 48.

    Toosi MN, Ardekani MRS, Minaie MB, Nazim I, Esfahani MM, Khadem E. Fatty liver disease from the perspective of traditional Iranian medicine. Quran Med. 2012;1(4):117-8.

  • 49.

    Emtiazy M, Keshavarz M, Khodadoost M, UniversityTehran S, Kamalinejad M, Gooshahgir S. Relation between body humors and hypercholesterolemia: An Iranian traditional medicine perspective based on the teaching of Avicenna. Iran Red Crescent Med J. 2012;2012(3):133-8.

  • 50.

    Kanter M, Coskun O, Budancamanak M. Hepatoprotective effects of Nigella sativa L and Urtica dioica L on lipid peroxidation, antioxidant enzyme systems and liver enzymes in carbon tetrachloride-treated rats. World J Gastroenterol. 2005;11(42):6684-8. [PubMed: 16425366].

  • 51.

    el-Dakhakhny M, Mady NI, Halim MA. Nigella sativa L. oil protects against induced hepatotoxicity and improves serum lipid profile in rats. Arzneimittelforschung. 2000;50(9):832-6. doi: 10.1055/s-0031-1300297. [PubMed: 11050701].

  • 52.

    Meral I, Yener Z, Kahraman T, Mert N. Effect of Nigella sativa on glucose concentration, lipid peroxidation, anti-oxidant defence system and liver damage in experimentally-induced diabetic rabbits. J Veterinar Med Physiol Pathol Clinic Med. 2001;48(10):593-9.

  • 53.

    Suriyavathana Vedanarayanan M, Krishnan N. Ayurvedic formulation of Liv-Pro-08 reduces nonalcoholic fatty liver disease in rats fed with high-fat diet. J Acupunct Meridian Stud. 2011;4(4):236-41. doi: 10.1016/j.jams.2011.09.014. [PubMed: 22196506].

  • 54.

    Jun HJ, Lee JH, Jia Y, Hoang MH, Byun H, Kim KH, et al. Melissa officinalis essential oil reduces plasma triglycerides in human apolipoprotein E2 transgenic mice by inhibiting sterol regulatory element-binding protein-1c-dependent fatty acid synthesis. J Nutr. 2012;142(3):432-40. doi: 10.3945/jn.111.152538. [PubMed: 22279139].

  • 55.

    Chung MJ, Cho SY, Bhuiyan MJ, Kim KH, Lee SJ. Anti-diabetic effects of lemon balm ( Melissa officinalis) essential oil on glucose- and lipid-regulating enzymes in type 2 diabetic mice. Br J Nutr. 2010;104(2):180-8. doi: 10.1017/S0007114510001765. [PubMed: 20487577].

  • 56.

    Zarei A. The Effects of Hydroalcoholic Extract of Melissa officinalis. L on the Level of Renal Function and Liver Enzymes in Diabetic Rats. Iran J Endocrinol Metabol. 2016;17(5):353-61.

  • 57.

    Kim J, Lee H, Lim J, Oh J, Shin SS, Yoon M. The Angiogenesis Inhibitor ALS-L1023 from Lemon-Balm Leaves Attenuates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease through Regulating the Visceral Adipose-Tissue Function. Int J Mol Sci. 2017;18(4). doi: 10.3390/ijms18040846. [PubMed: 28420164].