Effect of Nigella sativa on thyroid function in patients with hypothyroidism treated with levothyroxine: a triple-blind randomized controlled trial Medical Science

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CLINICAL TRIAL
Effect of Nigella sativa on thyroid function in
patients with hypothyroidism treated with
levothyroxine: a triple-blind randomized
controlled trial
Maryam Fatemi Tekieh1, Fatemeh Esfahanian2, Fatemeh Emadi1,3, Mohammad
Gholami4, Elham Emaratkar1
1Department of Traditional Medicine, School of Medicine, Shahed University, Tehran, Iran
2Department of Endocrinology, Imam Khomeini Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
3Traditional Medicine Clinical Trial Research Center, Shahed University, Tehran, Iran
4Department of Biostatistics, Tarbiat Modarress University, Tehran, Iran
Correspondence author
Department of Traditional Medicine, School of Medicine,
Shahed University, Tehran,
Iran
Email: elhamemaratkarmd@yahoo.com
Article History
Received: 06 April 2019
Accepted: 13 June 2019
Published: July - August 2019
Citation
Maryam Fatemi Tekieh, Fatemeh Esfahanian, Fatemeh Emadi, Mohammad Gholami, Elham Emaratkar. Effect of Nigella sativa on
thyroid function in patients with hypothyroidism treated with levothyroxine: a triple-blind randomized controlled trial. Medical
Science, 2019, 23(98), 606-614
Publication License
This work is licensed under a Creative Commons Attribution 4.0 International License.
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Article is recommended to print as color digital version in recycled paper.
RESEARCH 23(98), July - August, 2019
Medical Science
ISSN
2321–7359
EISSN
2321–7367

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ABSTRACT
Background: Hypothyroidism is a common endocrine disorder and a risk factor for cardiovascular disease, despite the treatment with
classic medicine; the symptoms are not completely eliminated. Nigella sativa is an effective herbal medicine in traditional medicine
that used for a variety of metabolic diseases and cold nature. Objective: The aim of this study was to investigate the effect of N.
Sativa on thyroid function in hypothyroidism. Materials and methods: The present study is a triple-blind randomized controlled trial
conducted on 42 patients (16-65 years of age) with hypothyroidism treated with levothyroxine in Imam Khomeini Hospital in Tehran
during 2017- 2018, and were randomly allocated into two groups of intervention and control receiving powdered N. Sativa or
placebo daily for two months and changes in thyroid status and lipid and glucose profile after 2 months were measured. Results: 22
patients were analyzed in the intervention group and 20 in the placebo group. The results showed that there was no significant
difference between the intervention group and the placebo group (p=0.02). Significant decreases in total cholesterol and fasting
blood sugar (FBS) were observed in patients with negative anti-thyroid peroxidase (Anti-Tpo) antibodies. In patients with positive
Anti-Tpo antibodies, a significant increase in total cholesterol and FBS were observed in the intervention group (p=0.02). 5 patients
in the intervention and placebo groups experienced mild and temporary side effects. Conclusion: N. sativa is used in Persian
medicine to treat the disorders due to cold nature, and its consumption is increasing due to its native and safe nature and its low
cost and effectiveness. Nevertheless, its function on human thyroid requires more trials and it should be used with caution.
Keywords: Clinical trial, Hypothyroidism, Nigella sativa, Black cumin Persian medicine, Nature
1. INTRODUCTION
Hypothyroidism is a common endocrine disorder in the world. It is considered as a cause of morbidity and mortality due to its
association with metabolic diseases, especially in old age (Delshad et al., 2012). 5 % of the population over 12 years old in the United
States have hypothyroidism (Mahan et al., 2012). The prevalence of hypothyroidism in countries with adequate iodine intake has
been reported to be between 1-2%, and up to 7% at high ages. The prevalence of hypothyroidism in women is several times higher
than that of men (Taylor et al., 2018).
Subclinical hypothyroidism has been reported between 4% and 20% in women and elderly people (Paz-Filho et al., 2018). It is 20
times more common than overt hypothyroidism (Mc Aninch et al., 2016). The most common cause of hypothyroidism is primary
hypothyroidism, and in the context of self-immune process (Ke et al., 2015).
Clinical symptoms are related to the degree of hypothyroidism and are non-specific symptoms, which include fatigue, cold
sensitivity, constipation, dry and rough skin, paleness, brittle nails and hair, puffy face, weight gain, increased rigidity, pain and
weakness of the joints, menorrhagia, and depression (Rugge et al., 2016; Cheng F-K, 2018; Jonklaas et al., 2014). Hypothyroidism is
known as a risk factor for cardiovascular disease and is associated with metabolic syndrome (Mehran et al., 2017). Several studies
have shown that hypothyroidism is associated with an increase in the number and severity of depression and its effect on quality of
life (Najafi et al., 2015). Despite the fact that levothyroxine is considered to be a standard treatment for hypothyroidism due to its
ease of usage, high half-life in the body, low cost, and acceptable complications, but 10% - 15% of patients are dissatisfied with the
treatment with levothyroxine because of the persistence of hypothyroidism symptoms and 15% of patients do not reach normal T3
levels (McAninch et al., 2015). In 40% of patients treated with levothyroxine, TSH do not reach the appropriate range, and 40% of the
rest, especially at high ages, have lower TSH than normal (Paz-Filho et al., 2018). Even in patients with normal TSH, the symptoms of
hypothyroidism still remain. New researches reported that levothyroxine mono therapy is inadequate in treating hypothyroidism
symptoms, especially psychological symptoms, and despite the normal serum thyroid hormone levels, they report hypothyroidism in
the tissues. Today, the probable role of Personalized Medicine based on the genotype is emphasized in the treatment of untreated
cases (McAninch et al., 2015). According to the World Health Organization, 80% of the population use traditional methods for
treatment (Amin et al., 2015). Considering that treatment in Persian medicine (PM) is based on the nature of individuals, and this
medicine is growing more popular, it may be helpful in the treatment of hypothyroidism which symptoms are similar to the cold
nature. Therapeutic management in Persian medicine may improve the symptoms of hypothyroidism, and administration of warm
medicines, such as N. sativa with anti-inflammatory properties, seems to be beneficial in the treatment of this disease (Farhangi et
al., 2016; Pakdel et al., 2017; Khalawi et al., 2013). N. sativa seed or black cumin (Family Ranunculaceae) is an annual herb, which has
been used traditionally for thousands years. N. sativa seed reveal an expand therapeutic activities including anti-diabetic, anti-

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cancer, immune regulating, analgesic, anti-microbial, anti-inflammatory, spasmolytic, bronchodilator, hepato protective, renal
protective, gastro protective, anti-oxidant effects (Shariatifar et al., 2014; Ahmad et al., 2013; Islam et al., 2017; Eftekharafzali et al.
2018; Falahieh et al. 2019). Several animal studies have reported its beneficial effects on hypothyroidism and have proven their
efficacy (Pakdel et al., 2017; Khalawi et al., 2013; Shariatifar et al., 2014), but human studies in this field are very limited and there is
not enough evidence for the effect of N. sativa on human hypothyroidism. Therefore, we decided to evaluate the effect of N. sativa
on hypothyroid patients by performing a clinical trial. Several human studies confirm that N. Sativa has no major adverse effects or
toxicity (Islam et al., 2017; Sultan et al., 2014).
2. MATERIALS AND METHODS
This study is a triple-blind randomized controlled trial. The aim of this study was to investigate the effect of N. sativa in improving
thyroid function in patients with hypothyroidism in Tehran, Iran (2017-2018). The participants of this study were patients with
hypothyroidism treated with levothyroxine who had been referred to Endocrine and Metabolism Clinic of Imam Khomeini Hospital in
Tehran and had TSH levels greater than 2µIU/ml and less than 10µI U/ml in at least 2 consecutive visits.
The inclusion criteria for this study include:
1. Patients with hypothyroidism treated with levothyroxine that have TSH greater than 2 and less than 10 in at least 2
consecutive visits by an endocrinologist.
2. Over 16 and under 65 years of age
3. Having a willingness to participate in the study and signing a written consent.
Exclusion criteria include:
1. Heart disease, coagulopathy, other autoimmune disorders, pituitary and hypothalamic problems, and kidney and malignant
diseases,
2. Participation in another study
3. Use of supplemented food with drug interaction
4. Pregnancy and lactation
5. Receive any nutritional supplement during the study
6. Unwillingness to continue cooperation
7. A history of allergy to N. sativa.
In this study, 100 patients were evaluated for inclusion criteria from which 52 were found eligible to enter the study and
expressed their satisfaction to participate in the study After responding to the demographic questionnaire and undertaking the
measurement of height, weight, and vital signs, blood samples were obtained to determine the baseline amount of FT4, T3, TSH,
Anti-Tpo, Total cholesterol, FBS, HDL-C, LDL-C, and TG.
The serum and plasma samples were separated by centrifugation at 2500 rpm for 10 min (Beckman Avanti J-25; Beckman
Coulter, Brea, CA, USA) at room temperature. The serum samples were stored at −70 °C immediately. The reference values for TSH
and free T4 were 0.4 to 6/1 mUI/mL and 0.8 to 2 ng/dL, respectively and T3 0/6 to 2/2ng/dL. The Anti-TPO levels > 40 UI/mL were
considered positive. And then TSH, T3 and FT4 were measured by IRMA kit and anti-TPO by enzyme linked immune sorbent assay
(ELISA).
In this study the weight, height, vital signs and FT4, T3, TSH, Anti-TPO, Total cholesterol, FBS, HDL-C, LDL-C and TG were
measured in the first visit and the end of the eighth week. The primary outcome of this study was the levels of FT4, T3, TSH, Anti-tpo,
and secondary outcomes of this study was the serum levels of Total cholesterol, FBS, HDL-C, LDL-C, TG, and vital sign, and BMI. This
study with IR.shahed.REC.1396.125 code was approved by the Medical Ethics Committee of Shahed University. It has also been
registered and approved at the Iranian Registry of Clinical Trials with IRCT20171113037424N2 registration code.
Drug and placebo preparation
The N. sativa seeds were purchased from the local market (Attari), Tehran, Iran. The seeds were authenticated and deposited at
Herbarium of Faculty of Pharmacy, Tehran University of Medical Sciences with voucher no. PMP-1712. Then, N. sativa seeds were
crushed with grinder and then filled in 500 mg capsules. The placebo was prepared from corn starch colored with edible food
coloring. The medication was provided in identical 500 mg capsules, containing either powdered N. sativa seed or placebo. The
participants received either N. sativa or placebo, 2 times a day, each time 2 capsules, before breakfast and half an hour after
levothyroxine pill.

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Statistical analysis
In this study, descriptive analysis (means ±SD, correlation, frequency and percent) and inferential analysis (chi-square test,
independent t-test, Mann-Whitney test, depended t-test,) and Kolmogorov–Smirnov test (for normality and non-normality
distribution test) were used. Data were analyzed using SPSS, version 21. A probability of less than 0.05 was considered as significant.
A total of 20 samples was calculated for each group using the formula, n=2(Z_(α/2) + Z_β) ^2/d^2, in which α=0.05, β=0.1 and d=1.
3. RESULTS
In this study 52 patients passed the inclusion criteria and entered the study. After allocation in two groups, 10 subjects were unable
to continue the study (Figure 1). The mean and SD for age and BMI in addition gender presented in table 1. As it is shown in this
table no significant differences were observed between drug and placebo groups.
Figure 1 Follow up diagram
Table 1 The mean and SD of age and BMI according to the two groups
Group
P-value
Placebo
Drug
n
%
N
%
Anti Tpo<40
Female
3
100.0%
7
100.0%
>0.999
Male
0
.0%
0
.0%
Anti Tpo>40
Female
9
90.0%
11
91.7%
>0.999

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Male
1
10.0%
1
8.3%
Mean
SD
Mean
SD
Anti
Tpo<40
Age
40.67
12.42
46.00
9.87
0.485
BMI
31.14
1.17
33.28
5.85
0.560
Anti
Tpo>40
Age
42.70
11.33
43.42
10.24
0.878
BMI
30.78
6.33
30.54
4.44
0.918
SD: Standard Deviation,
P-value base on chi-square test for categorical variable and T-test or Mann-Whitney U test for continues variables
The results showed that in patients who had Anti-Tpo <40 at the beginning of the study: TSH in the placebo group showed a
significant increase (+0.74, p value <0.001). In patients with Anti Tpo >40, Log Anti-Tpo variable increased and decreased
significantly in the intervention group (+0.06, p value = 0.02), and the placebo group (-0.04, p value = 0.015), respectively. Also, TG
increased significantly in the placebo group (+18.2, p value = 0.019) and Chol T, LDL-C, HDL-C, and FBS had no significant change in
the two groups (Table 2 and Figure 2).
Table 2 The Mean and SD of variable before and after of study according to the groups
Variables
Group
Pre
Post
Difference
P-value
Mean
SE
Mean
SE
Anti Tpo<40
FT4
Placebo
1.05
0.05
1.15
0.04
0.1
0.003
Drug
1.08
0.05
1.06
0.04
-0.02
0.784
T3
Placebo
141.72
3.4
130.6
7.49
-11.12
0.338
Drug
138.36
3.85
130.99
2.64
-7.37
0.112
TSH
Placebo
4.02
0.57
4.76
0.5
0.74
0.001
Drug
4.58
0.55
4.25
0.74
-0.33
0.453
Log Anti
TPO
Placebo
0.82
0.17
0.82
0.12
0
0.982
Drug
0.88
0.1
0.92
0.09
0.04
0.282
Chol
Placebo
171
14.59
174.33
13.03
3.33
0.650
Drug
171.14
5.56
157.43
7.28
-13.71
0.009
FBS
Placebo
83.67
7.94
95
11.07
11.33
0.066
Drug
104.43
5.82
99
4.28
-5.43
0.033
HDL
Placebo
40.33
3.9
47.33
4.57
7
0.041
Drug
46.43
1.72
44
1.47
-2.43
0.029
TG
Placebo
165.33
11.98
122
10.28
-43.33
0.056
Drug
119.29
13.14
108.71
9.65
-10.58
0.249
LDL
Placebo
97.33
12.99
102
10.89
4.67
0.571
Drug
100.57
5.56
95.71
7.62
-4.86
0.106
Anti Tpo>40
FT4
Placebo
1.02
0.04
1.04
0.03
0.02
0.430
Drug
0.95
0.04
0.98
0.06
0.03
0.649
T3
Placebo
136.18
3.93
135.98
2.79
-0.2
0.963
Drug
132.07
3.38
131.66
5.19
-0.41
0.917
TSH
Placebo
4.87
0.47
3.8
0.77
-1.07
0.061
Drug
4.96
0.59
5.83
0.54
0.87
0.170
Log Anti
TPO
Placebo
2.16
0.06
2.12
0.06
-0.04
0.015
Drug
2.38
0.09
2.44
0.09
0.06
0.020
Chol
Placebo
165.6
12.18
152.9
7.43
-12.7
0.066
Drug
165.75
10.2
161.75
7.88
-4
0.483
FBS
Placebo
113.2
2.58
113
2.99
-0.2
0.951

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Drug
106.42
9.75
113.33
15.03
6.91
0.298
HDL
Placebo
42
0.96
40.4
1.27
-1.6
0.253
Drug
42.42
1.88
41.75
1.95
-0.67
0.465
TG
Placebo
105.3
11.06
123.5
14.36
18.2
0.019
Drug
139.42
24.26
135.67
16.11
-3.75
0.764
LDL
Placebo
90.1
6.12
87.3
6.32
-2.8
0.519
Drug
95.08
8.02
92.58
6.93
-2.5
0.579
SE: Standard Error of Mean. P-value base on Paired Sample t-test or Wilcoxon Signed Ranks Test
T3
Pretest-Placebo
Posttest-Placebo
Pretest-Drug
Posttest-Drug
0
50
100
150
FT4
Pretest-Placebo
Posttest-Placebo
Pretest-Drug
Posttest-Drug
0.0
0.5
1.0
1.5
TSH
Pretest-Placebo
Posttest-Placebo
Pretest-Drug
Posttest-Drug
0
2
4
6
AntiTpo
Pretest-Placebo
Posttest-Placebo
Pretest-Drug
Posttest-Drug
0
50
100
150
200
250
Figure 2 The Mean of variable before and after of study according to the groups
In the N. sativa group, five patients had complications (stomach pain (2 female), headache, and hypertension (1 female),
bloating, and increased appetite (1 female) spotting (1 female). Also in the placebo group, five patients had complications: severe
weakness (1 female), stomach pain (1 female), bloating (1 female), headache, and stomach pain (1 female), headache (1 female).

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4. DISCUSSION
The present study showed that use of N. sativa along with levothyroxine for 8 weeks in hypothyroid patients had no significant
effect on thyroid function and in patients with positive Anti-Tpo marker led to a significant increase in inflammatory marker
compared to the control group.
Despite the fact that most animal studies in recent years reported the positive effect of N. sativa on thyroid function in
hypothyroidism (Pakdel et al., 2017; Khalawi et al., 2013; Shariatifar et al., 2014), this study contrasted with the findings of previous
studies and for the first time demonstrated the effect of N. sativa on increasing thyroid inflammatory markers in humans. It is
probably opposed to studies that recommended the use of N. sativa as an anti-inflammatory drug (Hayatdavoudi et al., 2016; Butt
and Sultan, 2010; Arjumand et al., 2019; Bashir et al., 2014; Al-Ghamdi et al., 2001) and a protector of thyroid against anti-thyroid
drugs. The effects of fasting blood glucose and blood cholesterol reduction in the patient with negative anti-tpo in the N. sativa
group compared to the control group were in agreement with the study of Amini and Hadi and others (Kaatabi et al., 2012; Sharif et
al., 2012; Heshmati and Namazi, 2015; Pelegrin et al., 2019). Farhangi et al. reported a beneficial effect of N. sativa on Hashimoto's
Thyroiditis (Farhangi et al., 2016). However, in the present study, not only Hashimatho patients but also all patients with negative
and positive anti tpo hypothyroidism entered the intervention.
Various animal studies reported that there is a relationship between the anti-inflammatory effects of N. sativa and the reduction
of NO, IL-1, COX-1, COX-2, and HDOC production, and pre-inflammatory mediators such as IL-1b, IL-6, TNF-α, IFN-γ, and PGE2
(Islam et al., 2017).
In this study, it seems that several factors are effective in producing negative results including concurrent use of N. sativa and
levothyroxine together in the morning. Because the concurrent use of the herbal and chemical drugs is likely to cause drug
interaction. The use of N. sativa and levothyroxine in the morning (With emphasis on fasting and intervals in drug usage) may lead
to a greater reduction in the absorption of levothyroxine in the N. sativa group than the placebo group. Therefore, it is suggested
that in future studies, the intervention drug be given at noon to prevent its interaction with levothyroxine. The length of the study in
both the warm and cold seasons causes changes in the thyroid hormone, as the ambient temperature affects the results of the
thyroid test (Bobek et al., 1980; Donkoh A, 1989; Magdub et al., 1982; Saber et al., 2009). The lack of evaluation and control of the
diet of patients is effective in the results of thyroid tests (Paz-Filho et al., 2018). In the animal study of Parvinru (Parvinroo et al.,
2014) and human study of Mohammadi (Mohammadi et al., 2014) the effects of warm nature diet on increasing levels of thyroid
hormones were reported. It seems that the use of corn starch as a placebo in studies is inappropriate because its anti-inflammatory
effects have been reported in several studies (Grases et al., 1993; Goren et al., 2018; Rossaint et al., 2014) and in the present study,
its effect on thyroid inflammation and competition with N. sativa is evident. The N. Sativa, which has a high degree of warmth, can
boost the immune system and increase Anti-Tpo.
The diagnosis and current treatment of thyroid disease are based on laboratory findings, and the treatment of this disease is
done exclusively by medicine. While complex interventional factors including individual, dynamic, and adaptive factors such as
genetic, epigenetic, allostatic factors, obesity, age, and mental illness, etc., are effective in linking thyroid stimulating hormone and
thyroid hormone regulation and affect the pattern of diagnosis and treatment (Hoermann et al., 2017). Mental (Sina I, 2005) dietary
factors (Mezzomo et al., 2016; Pałkowska-Goździk et al., 2018) massage (Fielda T, 2016), and climate change interfere with the
treatment of this disease, in addition to factors such as age, sex, and body weight (Hoermann et al., 2017).
In Persian medicine, there are three main steps of treatment: 1- Lifestyle management, especially nutrition 2- Proper drug use 3-
massage and cupping and other manipulation methods (Sina I, 2005). Lifestyle modification is an important treatment method
before medical treatment, and includes management in the six main principles of Weather, Nutrition, Physical activity, Psychic
features, Sleep and awareness, and Excretion of body wastes materials and retention of necessary material (Ansaripour et al., 2019).
If we can increase the thyroid gland secretion with persian medicine and improve lifestyle, or improve the mechanisms responsible
for the deficiency of thyroid hormone secretion, it seems that we will have better effects and fewer symptoms of hypothyroidism
than levothyroxine and N. sativa or other herbal drugs. It is suggested that in future studies, formulations other than N. sativa
powder, such as N. sativa oil, should be used and measured with different doses.
Limitations
Conflicting variables such as psychological state, diet, and the rate of exercise of patients may affect thyroid function tests and the
results of the study.

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5. CONCLUSION
The results of this study showed that daily use of 2 grams of N. sativa alone could not improve thyroid profiles in patients with
hypothyroidism. Therefore, in accordance with the Iranian traditional medicine, lifestyle modification is the most important step in
the treatment, in the treatment of these patients, management of the 6 principles for health (Setteh Zarorieh) to improve lifestyle
along with drug therapy is recommended.
Conflicts of interest
There is no conflict of interest.
Financial resources
There is no financial resource.
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