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Research Article

Open Access

Efficacy and safety of Citrus sudachi peel in obese adults:
A randomized, double-blind, pilot study
Masashi Akaike1, Ken-ichi Aihara2, Hiroaki Yanagawa3, Takashi Iwase4, Sumiko
Yoshida2, Chiho Sato3, Tomoka Saijo3, Hiroaki Mikasa5, Yoshizaki Kashiwada6,
Yoshihisa Takaishi6, Koichiro Tsuchiya7, Toshiaki Tamaki8, Toshio Matsumoto2,
Masataka Sata4
1

Department of Medical Education, 2Department of Medicine and Bioregulatroy Sciences,4
Department of Cardiovascular Medicine, 6Department of Natural Medicines, 7Department ofMedical Pharmacology, 8Department of Pharmacology, The University of Tokushima
Graduate School of Medical Sciences, 3Clinical Trial Center for Developmental Therapeutics,
Tokushima University Hospital, 5Support Center for Medical Education, School of Medicine,
The University of Tokushima, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan
Correspondence author: Masashi Akaike, MD, PhD. Department of Medical Education,
University of Tokushima Graduate School of Medical Sciences, 3-18-15 Kuramoto-cho,
Tokushima 770-8503, Japan
Submission date: May 9, 2014; Acceptance date: June 27, 2014; Publication date: July 1,
2014

ABSTRACT
Objective: This study was undertaken to explore the efficacy and safety of Citrus sudachi
peel for metabolic risk factors in obese male and female adults.
Background: Citrus sudachi Hort. ex Shirai (Rutaceae), called “sudachi”, is a small, round,green citrus fruit that is mainly cultivated in Tokushima Prefecture in Japan. Our groupreported that Citrus sudachi peel powder improved glucose tolerance and dyslipidemia in
Zucher-fatty rats and reduced hyperglycemia and hypertriglyceridemia in GK diabetic rats.
Materials and Methods: We conducted a randomized, double-blind, placebo-controlled trial
in 40 participants with abdominal obesity and metabolic risk factors including hypertension,
impaired glucose tolerance and elevated triglyceride levels. Participants were randomized toreceive either tablets that contained 1.3 g dried Citrus sudachi peel powder or placebo tablets
for 12 weeks. The sudachi peel group included 14 males and 5 females with a mean age of
54.5 years, and the placebo group included 18 males and 2 females with a mean age of 51.9
years.
Results: Physical status including body weight, waist circumference and blood pressure andlaboratory markers including metabolic parameters were not different at any observation point
between the two groups. However, among participants with serum triglyceride levels of more

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than 120 mg/dl, body weight, waist circumference and serum triglyceride levels weresignificantly decreased at several observation points after the start of treatment in the sudachi
peel group but not in the placebo group. No serious adverse events were observed in thesudachi peel group.
Conclusions: Citrus sudachi peel has the potential effect to safely improve abdominal obesityand lower serum levels of TG in obese individuals with hypertriglyceridemia. A large-scalerandomized, double-blind clinical study targeting subjects with both abdominal obesity andhigh TG levels is needed to confirm the metabolic effects of Citrus sudachi peel.
Trial registration: UMIN Clinical Trials Registry (UMIN-CTR) UMIN000002682.
Accession number of the Ethics Committee for Clinical Trials of Food in Tokushima
University Hospital is F5.
Key words: health functional food, anti-obesity, triglyceride
BACKGROUND:
Citrus sudachi Hort. ex Shirai (Rutaceae), called “sudachi”, is a small, round, green citrus
fruit that is mainly cultivated in Tokushima Prefecture in Japan [1]. Slices of this fruit areoften used for Japanese dishes as food flavoring in place of vinegar and the peel is also edible.
Our group reported that Citrus sudachi peel powder improved glucose tolerance anddyslipidemia in Zucher-fatty rats and reduced hyperglycemia and hypertriglyceridemia in GK
diabetic rats [2]. However, the effects of Citrus sudachi peel on lifestyle-related risk factors inhumans have not been clarified. Metabolic syndrome is a combination of lifestyle-related risk
factors that increase the risk of developing cardiovascular disease and diabetes [3]. The aim of
this study was to explore the efficacy and safety of Citrus sudachi peel for improving
lifestyle-related risk factors including obesity, hypertension, impaired glucose tolerance anddyslipidemia in humans.
METHODS:
Subjects: Inclusion criteria were males and females aged 20 - 74 years who had abdominal
obesity defined as waist circumference >85cm for males or >90cm for females or body massindex (BMI) >25 and any one of the following: 1) fasting plasma glucose (FPG) >100 mg/dL(5.6 mmol/L) or specific treatment for type 2 diabetes, 2) serum triglycerides (TG)>150 mg/dL (1.7 mmol/L) or high-density lipoprotein cholesterol (HDL-C) <40 mg/dL(1.03 mmol/L) or specific treatment for its abnormality, and 3) systolic blood pressure (BP)>130 or diastolic BP >85mmHg or treatment of hypertension. The following subjects were
excluded: 1) subjects with complications in the brain, heart, kidney, lungs or liver(cerebrovascular accident, myocardial infraction, angina pectoris, history of cardiovascularintervention, heart failure, arteriosclerosis obliterans, nephropathy, bronchial asthma,
pulmonary emphysema, pneumonitis, pulmonary fibrosis, viral hepatitis, cirrhosis, diabetic
complications, and diabetes treated with insulin), 2) subjects in whom additional
pharmaceutical agents should be considered for hypertension, lipid disorder, diabetes mellitus
and/or other diseases, 3) subjects with overt systemic diseases, 4) subjects with a history ofmalignant diseases, 5) subjects who participated in another clinical trial, and 6) subjects who

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were not appropriate in the attending physicians' opinion.
Experimental design: This study was designed as a randomized, double-blind,placebo-controlled trial. Participants were randomized to receive either 5 tablets that in total
contained 1.3 g dried Citrus sud achi peel powder (sudachi peel group) or 5 placebo tablets(placebo group) every day for 12 weeks. Daily intake in the sudachi peel group was
equivalent to 1/3 of a whole Citrus sudachi. Since analysis carried out by the Japan Food
Research Laboratories showed that the content of synephrine in Citrus sudachi peel is 2.5
mg/g, estimated intake of synephrine, which is contained in abundance in citrus peel and has
pharmacological effects similar to those of ephedrine, was only 3.25 mg/day in the sudachi
peel group. Analysis carried out by the Japan Food Research Laboratories also showed thatthe content of hesperidin, a flavonoid found abundantly in citrus fruits, was 7.4 mg/g in Citrus
sudachi peel, indicating that the estimated intake of hesperidin was only 9.62 mg/day in thesudachi peel group. The study period was 17 weeks including a 1-week observation period
before treatment, 12-week treatment period with Citrus sudachi peel powder or placebo
tablets and 4-week observation period after treatment. The subjects made visits to the hospital
1 week before the treatment, 4, 8 and 12 weeks after the start of treatment, and 4 weeks after
the treatment period. A life diary including physical activity and exercise was recorded every
day during the study period and a diet diary including content of meals was recorded for threedays before each visit. The number of remaining tablets was checked at each point of visit toassess the compliance of subjects. Physical examination including measurements of height,
body weight, BMI, waist circumference, BP and pulse was performed at each visit. Urine andblood samples were drawn from the antecubital vein after an overnight fast at each visit.
Biochemical analysis: General laboratory tests were also carried out at each visit. The tests
included urinalysis to assess urinary protein, occult blood, urobilinogen, sugar and ketone
bodies, measurements of peripheral blood including white blood cells, red blood cells,
hemoglobin, hematocrit and platelets, assessment of liver function including measurements of
GOT, GPT, LDH, total bilirubin, alkaline phosphatase, γGTP, total protein and albumin,
assessment of renal function including measurements of BUN and creatinine, measurementsof electrolytes including sodium, potassium, chloride, and calcium concentrations, andassessment of metabolic function including measurements of low-density lipoprotein(LDL)-C, HDL-C, TG, FPG, HbA1c (National Glycohemoglobin Standardization Program),
immunoreactive insulin (IRI), and uric acid (UA). In addition, blood levels of remnant-likeparticles (RLP)-C, free fatty acid (FFA), high-sensitivity C-reactive protein (hs-CRP), tumor
necrosisfactor(TNF)-
andadiponectin
andurinary
excretionof8-hydroxy-2'-deoxyguanosine (8-OHdG) as a marker of oxidative stress were examined 1
week before treatment, 12 weeks after the start of treatment and 4 weeks after the treatment
period. Hs-CRP levels were measured at Bio Medical Laboratories (Tokyo, Japan) by
nephelometry, a latex particle-enhanced immunoassay (N Latex CRP II). TNF- was
measured by ELISA (Human TNF- TNFSF1A, R&D Systems, Inc., Minneapolis, USA).
Adiponectin was measured by ELISA (Human adiponection ELISA Kit, Otsuka
Pharmaceutical Co., Ltd, Tokyo, Japan). Urinary excretion of 8-hydroxydeoxyguanosine(OHdG) was determined by ELISA (new 8-OHdG Check ELISA Kit, Japan Institute for theControl of Aging, Nikken SEIL Corporation, Shizuoka, Japan) and expressed in g/g

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creatinine after correction by urinary creatinine concentration.
Ethics: The present clinical study is in compliance with the Helsinki Declaration. Prior
written informed consent was obtained from all subjects before enrollment in this study inaccordance with protocols approved by the Ethics Committee for Clinical Trials of Food inTokushima University Hospital (accession number F5). This study was registered in the
UMIN Clinical Trials Registry (UMIN-CTR) with the trial number of UMIN000002682.
Statistical Analysis: All parameters before and after treatment were compared between thesudachi peel group and the placebo group using generalized linear mixed model analysis.
Differences in baseline patient characteristics between the two groups were analyzed by the
unpaired t-test. The Wilcoxon signed rank test was used to assess significant changes inparameters after the start of treatment in each group. All data are expressed as means ± S.D.
The analyses were performed on a Microsoft Windows computer running SPSS software.
Differences were considered statistically significant at p < 0.05.
RESULTS:
Basal characteristics: Forty subjects were enrolled in this study, but one subject could not
visit our hospital due to personal reasons. Finally, the sudachi peel group included 14 males
and 5 females with a mean age of 54.5 years (one patient having dropped out), and theplacebo group included 18 males and 2 females with a mean age of 51.9 years. The patients’characteristics are summarized in Table 1. The first, second and third quartile of TNFα levels
is 1.3, 3.4 and 4.7 pg/mL in the placebo group, respectively, and 2.1, 2.3 and 3.2 pg/mL in the
Sudachi peel group, respectively. There were no differences in basal parameters including age,sex, BMI, waist circumference, pulse, BP, TG, HDL-C, HbA1c and FPG between the sudachi
peel group and the placebo group.
Intake rate of tablets: There was no difference between the intake rates of tablets in the twogroups (95.36.7 % in the sudachi peel group and 96.16.0 % in the placebo group).
Live and diet diary: Physical activity and dietary intake of total calories and nutrients
including carbohydrates, proteins and lipids were not different before, during and after
treatment in either the sudachi peel group or placebo group. There were also no differences inthese parameters at every observation point between the two groups.
Changes in parameters before, during and after treatment: Physical status including bodyweight, BMI, waist circumference, pulse and BP and laboratory markers including urinalysis,
peripheral blood, liver function, renal function, electrolytes, LDL-C, TG, HDL-C, RLP-C,
FFA, HbA1c, FPG, IRI, UA, hs-CRP, urinary 8-OHdG, TNF- and adiponectin were notdifferent at any observation point between the two groups. There were also no differences intheses parameter before and 4, 8 and 12 weeks after the start of treatment and at 4 weeks after
the treatment period in either the sudachi peel group or placebo group.
Adverse effects: One patient in the placebo group developed dizziness and palpitation due toparoxysmal atrial fibrillation. None of the patients in the sudachi peel group showedFunctional Foods in Health and Disease 2014; 4(6):276-284

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expression or worsening of symptoms.
Table 1. Baseline parameters in all subjects
Variables

Placebo groupn=20

Sudachi peel group
n=19

Age

51.911.0

54.5  8.9

ns

Male : Female

18:2

14:5

ns

Body weight (kg)76.2 10.8

75.610.9

ns

BMI

26.2  3.4

26.8  3.0

ns

Waist circumference(cm)93.7  6.1

97.3  6.3

Ns

Pulse (bpm)

73.5  5.8

71.9  8.2

ns

Systolic BP (mmHg)

128.9  13.0

134.6  10.5

ns

Diastolic BP (mmHg)

82.3  6.2

87.9  8.3

ns

LDL-C (mg/dL)

134.7  25.2

140.8  20.4

ns

TG (mg/dL)

143.8  67.0

146.6  60.3

ns

HDL-C (mg/dL)

62.9  15.1

67.7  15.8

ns

RLP-C (mg/dL)

9.6  5.8

9.8  5.4

ns

FFA (Eq/L)

538.5  133.1

548.6  197.2

ns

HbA1c (%)

6.0  0.3

5.9  0.4ns

FPG (mg/dL)

112.2  13.3

108.7  14.1

ns

IRI (g/dL)

8.0  3.1

7.7  3.6

ns

UA (mg/dL)

6.2  1.4

5.8  1.0

ns

hsCRP (g/dL)

100  116

93  98

ns

U-8OHdG(g/gCr)

9.9  4.6

11.9  7.5

ns

TNFα (pg/mL)

4.0  4.1

6.2  15.4

ns

Adiponectin(g/mL)

6.1  2.3

6.5  2.4

ns

P-value

Analysis in a subgroup with serum TG levels of more than 120 mg/dL: Since none of theparameters were changed by treatment with Citrus sudachi peel, we next analyzed the data insubjects with serum TG levels of more than 120 mg/dl. Although age and blood pressure of
the sudachi peel subgroup with serum TG levels of more than 120 mg/dl were slightly higher
than those of the placebo subgroup with serum TG levels of more than 120 mg/dl, there wereno significant differences in other baseline parameters between the two subgroups (Table 2).
The first, second and third quartile of TNFα levels is 3.5, 4.1 and 5.9 pg/mL in the placebogroup, respectively, and 2.2, 2.7 and 3.2 pg/mL in the Sudachi peel group, respectively.

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Table 2. Baseline parameters in subjects with serum TG levels of more than 120 mg/dl
Variables

Placebo groupn=11

Sudachi peel group
n=11

Age

47.311.0

56.3  8.2

0.046

Male : Female

9:2

8:3

ns

Body weight (kg)79.1 12.9

76.911.9

ns

BMI

26.8  4.0

27.5  3.4

ns

Waist circumference (cm)95.4  6.8

99.1  6.3

ns

Pulse (bpm)

74.5  6.6

73.8  9.7

ns

Systolic BP (mmHg)

126.7  9.7

135.5  8.1

0.049

Diastolic BP (mmHg)

82.0  6.1

89.5  9.6

0.042

LDL-C (mg/dL)

138.6  27.8

143.4  21.5

ns

TG (mg/dL)

189.4  56.3

184.7  49.4

ns

HDL-C (mg/dL)

58.4  14.5

64.7  11.8

ns

RLP-C (mg/dL)

13.1  5.7

13.0  5.0

ns

FFA (Eq/L)

524.0  141.3

609.5  233.1

ns

HbA1c (%)

6.0  0.4

5.8  0.4ns

FPG (mg/dL)

110.4  13.0

104.6  4.4

ns

IRI (g/dL)

8.7  1.8

8.6  4.4

ns

UA (mg/dL)

6.0  1.6

5.8  1.2

ns

hsCRP (g/dL)

100  89

125  119ns

U-8OHdG(g/gCr)

13.6  8.5

10.5  5.7

ns

TNFα (pg/mL)

5.4  3.7

8.8  19.8

ns

Adiponectin(g/mL)

5.8  2.1

6.7  2.3

ns

P-value

In subjects with serum TG levels of more than 120 mg/dl, body weight significantly
decreased from 76.9±11.9 kg before treatment to 76.1±11.1 kg (p<0.05) and 76.0±11.1 kg(p<0.05) at 8 and 12 weeks after the start of treatment, respectively, and the decrease in bodyweight was maintained 4 weeks after the treatment period (75.6±11.4 kg, p<0.01 vs before thetreatment) in the sudachi peel subgroup, but no significant changes in body weight wereobserved in the placebo subgroup (Figure 1A).
Waist circumference also significantly decreased from 99.1±6.3 cm before treatment to97.5±6.8 cm (p<0.01) and 97.3±7.3 cm (p<0.05) at 8 and 12 weeks after the start of treatment,
respectively, in the sudachi peel subgroup with serum TG levels of more than 120 mg/dL but
not in the placebo subgroup (Figure 1B). Serum TG level also significantly decreased from
184.7±49.4 mg/dL before treatment to 158.1±40.7 mg/dL (p<0.05) at 8 weeks after the startof treatment and to 141.2±37.1 mg/dL (p<0.01) at 4 weeks after the treatment period in thesudachi peel subgroup (Figure 1C). However, no significant changes in serum TG levels wereobserved in the placebo subgroup with serum TG levels of more than 120 mg/dL (Figure 1C).

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However, there was no difference in these parameters at any observation point between thetwo groups.

Figure 1. Changes of parameters in the placebo subgroup (□) and the sudachi peel subgroup(■) with serum triglyceride levels of more than 120 mg/dL. Body weight was significantly
decreased at 8 and 12 weeks after the start of treatment and the decrease in body weight wasmaintained 4 weeks after the treatment period in the sudachi peel subgroup (A). Waist circumference
was also significantly decreased at 8 and 12 weeks after the start of treatment in the sudachi peel
subgroup (B). Serum triglyceride (TG) levels were significantly decreased at 8 weeks after the start oftreatment and at 4 weeks after the treatment period in the sudachi peel subgroup (C). Serum TG levels
after the start of treatment significantly decreased compared with the baseline level in the sudachi peelgroup (p<0.05) (C). All data are expressed as ratios to baseline level before the start of treatment andmeans ± SEM. * p<0.05 and ** p<0.01 vs before treatment.

DISCUSSION:
This study is the first randomized, double-blind, placebo-controlled trial to clarify the effects
and safety of Citrus sudachi peel in humans. We did not find any significant differences inclinical parameters between the placebo group and sudachi peel group in the present study.
However, subgroup analysis using serum TG levels showed that intake of Citrus sudachi peelsignificantly decreased body weight, waist circumference and serum TG level in subjects withserum TG levels of more than 120 mg/dL, but such decreases were not observed in theplacebo subgroup. On the other hand, the subgroup analysis did not show significant
differences in parameters at any observation point after the start of treatment between theplacebo group and the sudachi peel group. These findings suggested that number of enrolled
subjects in this study is too small to show a significant difference between the two groups.
In addition, Taskinen et al. reported that serum TG level in obese subjects is increased by the
combination of increased secretion and severely impaired clearance of TG-rich VLDL1
particles and that increased secretion of TG-rich VLDL1 particles is linked to increased liverand subcutaneous abdominal fat [4], indicating that obesity with high TG levels has ametabolic pathology different from that in other types of obese patients with normal TG
levels. Taken together, a large-scale clinical study enrolling obese subjects with high TG
levels should be designed to clarify the clinical effects of sudachi peel.
There are several reports about the effects of components in citrus peel on metabolic
syndrome. Hesperidin, a flavanone glycoside found abundantly in the peel of citrus fruits,
was reported to improve hypercholesterolemia, hypertriglyceridemia or fatty liver in rat
models [5,6]. Morand et al. reported that in healthy, middle-aged, moderately overweight men,

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orange juice decreases diastolic blood pressure and postprandially increases
endothelium-dependent microvascular reactivity [7]. In Morand’s study, daily intake ofhesperidin was 292 mg. However, in our study, estimated intake of hesperidin was quite
low (only 9.62 mg/day) in the sudachi peel group. Synephrine contained in the peel ofbitter orange citrus also has beneficial effect on obesity as a thermogenic agent like theaction of ephedrine. In our study, estimated intake of synephrine was only 3.25 mg/day.
Colker et al. conducted the first study on the effects of a bitter orange extract containing
58.5 mg p-synephrine and 528 mg caffeine daily on body fat loss and lipid levels in 20
overweight adult subjects [8]. A review of human studies on Citrus aurantium (bitterorange) extract and its primary protoalkaloid p-synephrine showed that products
containing a low dose of synephrine, such as in our study, have no anti-obesity effect [9].
Taken together, we speculate that the effect of Citrus sudachi peel on obesity and TG
levels may not be due to synephrine.
Nakagawa et al. identified sudachitin (4',5,7-trihydroxy-3',6,8- trimethoxyflavone)and 3¢-demethoxysudachitin from Citrus sudachi peel as the most active compoundswith antimicrobial activity against methicillin-resistant Staphylococcus aureus andHelicobacter pylori [10]. Yuasa et al. also reported that sudachitin inhibited nitric oxide
production by suppressing the expression of inducible nitric oxide synthase inlipopolysaccharide-stimulated macrophages, indicating that sudachitin has ananti-inflammatory effect [11]. However, no components having an anti-obesity effect or
TG-lowering effect have so far been identified from the peel of Citrus sudachi. Further
studies are needed to clarify the mechanisms by which the peel of Citrus sudachi
improves obesity and lowers serum TG levels.
In our study, there were no adverse effects of the intake of 1.3 g dried Citrus sudachi
peel every day for 12 weeks. There are concerns about side effects of citrus peel on the
cardiovascular system since it contains a large amount of synephrine with ephedrine-likeaction. In Guidelines for the Use of Synephrine in Natural Health Products revised byHealth Canada in 2010, 30 mg/day is the maximum allowable dose for total synephrine.
Peel of Citrus sudachi may be safe for consumption because it contains less synephrine
than that in other citrus peels. However, since the subjects of our study had no
cardiovascular complications, the safety for patients with cardiovascular diseases was notconfirmed. In addition, since the period of Citrus sudachi peel intake was only 12
weeks in our study, further study is needed to show the safety of long-term Citrus
sudachi peel intake.
CONCLUSIONS:
Citrus sudachi peel has the potential effect to safely improve abdominal obesity and lower
serum levels of TG in obese individuals with hypertriglyceridemia. A large-scale randomized,
double-blind clinical study targeting subjects with both abdominal obesity and high TG levels
is needed to confirm the metabolic effects of Citrus sudachi peel.
Competing interests: The authors have no financial interests or conflicts of interest.
Author’s contributions: All authors contributed to this study.
Abbreviations: BMI, body mass index; BP, blood pressure; C, cholesterol; FFA, free fattyacid; FPG , fasting plasma glucose; HDL, high-density lipoprotein; hs-CRP, high-sensitivity

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C-reactive protein; IRI, immunoreactive insulin; LDL, low-density lipoprotein; OHdG,
hydroxydeoxyguanosine; RLP, remnant-like particles; TG, triglycerides; TNF, tumor necrosis
factor; UA, uric acid
Acknowledgments and Funding: We thank Kazue Ishikawa for her technical assistance inmeasurements of TNF-, adiponectin and 8-OHdG. This study was funded by KTT
Corporation (Osaka, Japan). Tablets of Citrus Sudachi peel or placebo were synthesized andprovided by KTT Corporation.
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