Effect of Pomegranate Extract Consumption on Cardiovascular Disease Risk Factors, Stress Hormones, and Quality of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial

Abstract

Background: Pomegranate extract (PE) provides a rich and varied source of biophenols, which can act as powerful antioxidants. The most abundant being ellagitannins, anthocyanins, and ellagic and gallic acid derivatives.. Evidence suggests that pomegranate juice consumption may alleviate cardiovascular disease (CVD) risk factors. This exploratory study investigates the effect of PEconsumption on blood pressure (BP), insulin resistance (HOMA-IR), stress hormone levels (cortisol/cortisone) and quality of life in healthy human volunteers.
Methods: Seven males and 22 females(n = 29) participated in a double-blind, randomised, placebo-controlled exploratory study (BMI: 25.05 ± 3.91 kg/m², age: 34.5 ± 13.7 years). All participants consumed either one PE (Pomanox, Pomegreat) or a placebo capsule daily, after a meal, for 4 weeks. Dietary history and habits and the health related Quality of Life questionnaire (Rand 36) were recorded pre- and post-intervention. BP, salivary cortisol and cortisone levels (am, noon, and pm) were assessed byELISAs, and fasting blood was obtained at baseline and after 4 weeks to compare glucose, insulin and insulin resistance parameters.
Results: All participants randomised in the study completed the intervention.Systolic BP was significantly reduced following PE from 120.3 ± 13.3 to 115.6 ± 13.1 mmHg (P = 0.012). There was a reduction in the HOMA-IR levels from2.22 ± 2.62 to 1.61 ± 1.88 (P = 0.045), and glucose, insulin and uric acid alldecreased from baseline. No significant changes were recorded in volunteerstaking the placebo. PEconsumption caused a significant drop of salivary cortisol levels (am; 39.5 ± 19.6%, p < 0.001 and noon; 43.1 ± 32.3%, p = 0.016). The salivary cortisol/cortisone ratio was also significantly reduced (am from 1.11 ± 0.51 to 0.55 ± 0.26, p < 0.001, noon 1.57 ± 0.85 to 0.75 ± 0.72, p < 0.001 and pm; 1.22 ± 0.90 to 0.74 ± 0.59, p = 0.011). Physical (p = 0.018) and social functioning (p = 0.021), pain (p = 0.003), general health (p = 0.008) and overall Quality of Life score (p = 0.007) were significantly improved in those taking the PE capsules. The intervention was delivered successfully with no withdrawals.
Conclusions: These results suggest that PE intake rich in biophenolsmay ameliorate cardiovascular risk factors, reduce stress levels and improve perceived health related quality of life. The reduction in salivary cortisol levels may prove beneficial for people suffering from chronic stress. This exploratory study provides useful information required to conduct a definitive trial.
Keywords: Pomegranate; Cardiovascular risk factors; Blood pressure; Insulin sensitivity; Cortisol; Quality of life.
Citation: Angela Stockton., et al. “Effect of Pomegranate Extract Consumption on Cardiovascular Disease Risk Factors, Stress Hormones, and Quality of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial”. EC Nutrition 2.4 (2015): 396-411.
Trial Registration: This trial was registered with The Clinical Trials.gov as NCT02005939.

Full text

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Research Article
Angela Stockton1*, Emad ASAl-Dujaili1, Gordon J McDougall2, Isobel Davidson1, Sandra Drummond1 and Laura
Wyness1
1Dietetics, Nutrition and Biological Sciences, School of Health Sciences, Queen Margaret University, Scotland, United Kingdom
2The James Hutton Institute, Invergowrie, Scotland, United Kingdom
Received: September 30, 2015; Published: October 15, 2015
*Corresponding Author:
Angela Stockton, Dietetics, Nutrition and Biological Sciences, School of Health Sciences, Queen Margaret Uni-
versity, Edinburgh EH21 6UU, Scotland, United Kingdom.
Effect of Pomegranate Extract Consumption on Cardiovascular Disease Risk
Factors, Stress Hormones, and Quality of Life in Human Volunteers: An Exploratory
Randomised, Double-Blind, Placebo-Controlled Trial
Abstract
Background: Pomegranate extract (PE) provides a rich and varied source of biophenols, which can act as powerful antioxidants. The
most abundant being ellagitannins, anthocyanins, and ellagic and gallic acid derivatives.. Evidence suggests that pomegranate juice
 -
tion on blood pressure (BP), insulin resistance (HOMA-IR), stress hormone levels (cortisol/cortisone) and quality of life in healthy
human volunteers.
Methods: Seven males and 22 females(n = 29) participated in a double-blind, randomised, placebo-controlled exploratory study
(BMI: 25.05 ± 3.91 kg/m², age: 34.5 ± 13.7 years). All participants consumed either one PE (Pomanox, Pomegreat) or a placebo cap-
sule daily, after a meal, for 4 weeks. Dietary history and habits and the health related Quality of Life questionnaire (Rand 36) were
recorded pre- and post-intervention. BP, salivary cortisol and cortisone levels (am, noon, and pm) were assessed byELISAs, and fast-
ing blood was obtained at baseline and after 4 weeks to compare glucose, insulin and insulin resistance parameters.
Results:        
from 120.3 ± 13.3 to 115.6 ± 13.1 mmHg (P = 0.012). There was a reduction in the HOMA-IR levels from2.22 ± 2.62 to 1.61 ± 1.88 (P





the PE capsules. The intervention was delivered successfully with no withdrawals.
Conclusions: These results suggest that PE intake rich in biophenolsmay ameliorate cardiovascular risk factors, reduce stress levels


Keywords:
Pomegranate; Cardiovascular risk factors; Blood pressure; Insulin sensitivity; Cortisol; Quality of life
Citation:
Angela Stockton., et al-
mones, and Quality of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial”. EC Nutrition 2.4
(2015): 396-411.
Trial Registration: This trial was registered with The Clinical Trials.gov as NCT02005939.

Effect of Pomegranate Extract Consumption on Cardiovascular Disease Risk Factors, Stress Hormones, and Quality
of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial
397
Citation:
Angela Stockton., et al-
mones, and Quality of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial”. EC Nutrition 2.4
(2015): 396-411.

most CVDs can be prevented by addressing risk factors such as tobacco use, unhealthy diet and obesity, physical inactivity, high blood
pressure (BP), diabetes and raised lipids. Dietary factors represent a key component of the disease and choosing a diet rich in fruit and

Polyphenols are the most abundant antioxidants in the diet and are widespread in plants. Their total dietary intake could be as high

strongly supports a contribution of polyphenols to the prevention of CVD. Much of the evidence on the prevention of diseases by poly-
phenols is derived from in vitro or animal experiments, which are often performed with doses much higher than those to which humans
are exposed to through the diet. Biophenols can act as powerful antioxidants. The term biophenols provides a more comprehensive and
   -

Pomegranate (Punicagranatum            
biophenol-rich pomegranate products has increased in recent years. Pomegranate provides a rich and varied source of biophenols. Cur-
      
In vitro testing has
-


-


-
   -

Promising results have been reported from human clinical trials due to pomegranates antioxidant, anti-diabetic, anti-hypolipidae-

      
biophenols exhibit strong protective actions on many pathological conditions particularly those triggered by oxidative stress such as

      
progression of atherosclerosis and the ensuing potential development of coronary heart disease. Pomegranate juice has also been shown
to reduce both systolic and diastolic blood pressure, fasting plasma insulin and insulin resistance calculated as HOMA-IR in a group of



 

11HSD-1 activity could lead to novel methods of preventing CVD and associated risk factors. Tsang, Al-Dujaili., et al
consumption of pomegranate juice enhanced antioxidant status, reduced systolic blood pressure and waist circumference, with a reduc-
tion in the cortisol/cortisone ratio in both urine and saliva (possibly via inhibition of 11HSD-1 in the liver and adipose tissue).
Introduction

Effect of Pomegranate Extract Consumption on Cardiovascular Disease Risk Factors, Stress Hormones, and Quality
of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial
398
Citation:
Angela Stockton., et al-
mones, and Quality of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial”. EC Nutrition 2.4
(2015): 396-411.



found in pomegranates, have been developed as botanical dietary supplements to provide an alternative convenient form for consuming
 

levels and quality of life in apparently healthy human volunteers.
Study design
Supplements and placebo
Pomegranate extract analysis


Margaret University (QMU), Edinburgh, UK. Individuals with systemic disease, including heart disease and diabetes, allergic reactions,
immunological conditions, or were pregnant or breastfeeding were excluded. All participants provided written informed consent and
a lifestyle questionnaire to determine their eligibility. Participants were asked to complete a pre-intervention food frequency question-
naire to examine the amount and type of polyphenolic compounds typically consumed. All participants were asked to maintain their
-
signed to receive either onePE (PE) (POMANOX®, Probeltebio) or placebo capsule daily, after a meal, for four weeks. Participants were
asked to complete a 3-day food and alcohol record (completed for 2 weekdays and 1 weekend day) before the beginning of the interven-
tion and for the same days in week 4. The study was conducted at QMU and the protocol was approved by QMU Research Ethics Commit-
tee. This study was conducted according to the guidelines laid down in the Declaration of Helsinki and all procedures involving human

  
natural concentrated extract of the whole pomegranate (POMANOX®) and maltodextrin. The active ingredients, punicalagins, have


and 0.37 mg anthocyanins. The placebo capsule only contained maltodextrin to provide the same energy content as the PE capsules (6.52
kcal or27.28 kJ per capsule).

formic acid, vortex mixed to ensure dissolution and placed on a blood rotator at 45 rpm for 30 mins at 4ºC. After centrifugation (2780 X
g, 5 mins, 5ºC), the supernatants were removed to fresh tubes and the extraction repeated on the pellet. The two extractions were com-




UK). The PDAD scanned discrete channels at 280 nm, 365 nm and 520 nm. The samples were applied to a C18 column (Synergi Hydro

 
(electrospray ionisation) interface and analysed the samples in positive and negative ion mode. All data shown is in negative mode. There
Methods

Effect of Pomegranate Extract Consumption on Cardiovascular Disease Risk Factors, Stress Hormones, and Qual-
ity of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial
399
Citation:
Angela Stockton., et al-
mones, and Quality of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial”. EC Nutrition
2.4 (2015): 396-411.
All measurements were taken at baseline (week 0) and again on completion of the intervention period (week 4). Participants were
asked to fast for 12 hours beforehand, except for water, and refrain from alcohol or extra physical activity on the previous day. The
anthropometric measurements collected were body weight, measured on Salter scales; height is using a SECA Leicester stadiometer;
and waist circumference using a steel tape (6 mm x 2 mm). Body mass index (BMI) was calculated using the following standard equa-
tion: BMI (Kg/m2) = (weight Kg/ (height m)2
              
pressure (SBP), diastolic blood pressure (DBP) and pulse rate were recorded on an A and D Medical UA-767 Plus Digital Blood Pressure
Monitor (2005). Three readings of BP were taken while participants were seated at each visit and the mean was calculated.
Three fasting venous blood samples were taken from each participant and drawn into glucose, heparin and EDTA tubes, which were



     
  

calculated from fasting insulin and glucose concentration according to the formula: fasting insulin (µIU/mL) x fasting glucose (mmole/

Saliva samples were collected pre- and post-intervention at three time points during a single day (morning, noon and afternoon).
 
Dujaili., et al      


Self-rated health-related quality of life (HRQoL) was assessed at baseline and at 4 weeks via the Rand 36-item general health sur-

eight health concepts: physical functioning, role limitations caused by physical health problems, role limitations caused by emotional
problems, social functioning, emotional well-being, energy/fatigue, pain and general health perceptions as well as two summary scores:
physical and mental health. Scores for the eight scales were calculated according to the summative method of calculating the mean of

-

were examined using independent t tests with PE and placebo groups as the independent variables and age, gender, SBP, DBP, pulse rate,


-

were two scan events; full scan analysis followed by data-dependent MS/MS of the most intense ions using collision energies (source

Measurements
Statistics and analysis

Effect of Pomegranate Extract Consumption on Cardiovascular Disease Risk Factors, Stress Hormones, and Qual-
ity of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial
400
Citation:
Angela Stockton., et al-
mones, and Quality of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial”. EC Nutrition
2.4 (2015): 396-411.
Figure 1:
Flow diadram of the enrolment, randomisation and follow up of study participants.
                


  
      

A total of 31 volunteers were assessed for eligibility for inclusion to this study. Twenty-nine participants (7 males and 22 females)

between 19 and 62 years with a BMI between 18.5 and 32.7 kg/m2. Tables 1 and 2 show baseline characteristics of the participants
randomised to the PE capsules and the placebo (PL) capsules groups. The two groups were comparable on entry into the study with

Participants
Results
Characterisation of Pomanox extract

Effect of Pomegranate Extract Consumption on Cardiovascular Disease Risk Factors, Stress Hormones, and Qual-
ity of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial
401
Citation:
Angela Stockton., et al-
mones, and Quality of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial”. EC Nutrition
2.4 (2015): 396-411.
Figure 2:
Phenolic components in pomegranate study capsules. UV traces at 280 nm, placebo and study capsules

between the samples. A = placebo capsule and B = POMANOXcapsule.
Peak m/z [M-H] MS2Identification
1 1415* 1113, 933, 783, 781, 633 Di (HHDP galloyl glucose) pentose
2 783 481, 301, 275 Pendunculagin isomer
3 1083 781, 721, 601, 575 
4 951 907, 783, 301 
5 951 907, 783, 301 
6 1083 781, 721, 601, 575 
7 1085 785, 631, 451 Digalloylgallagyl hexoside
8 935 633, 301 
9 1567 N/A Sanguiin H10 isomer
10 633 463, 301 
11 463 301, 275 EA hexoside
12 447 301 EA rhamnoside
13 301 301, 275 Ellagic acid (EA)
Table 1: 
*possible punicalagin isomer in this peak; underlined = major MS2 fragments, N/A = MS2 not available. HHDP = hexahydroxy-
diphenoyl. unit

Effect of Pomegranate Extract Consumption on Cardiovascular Disease Risk Factors, Stress Hormones, and Qual-
ity of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial
402
Citation:
Angela Stockton., et al-
mones, and Quality of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial”. EC Nutrition
2.4 (2015): 396-411.
Effect on Anthropometric Measures

-
ference in either group over the 4 week intervention. A slight decrease in fat mass and slight increase in fat-free mass was found in both



Baseline (week 0) Post intervention (week 4) P value
Mean SD Mean SD
 70.07 13.70 70.39 13.78 0.233
BMI (kg/m2) 25.33 4.45 25.41 4.50 0.455
 0.82 0.13 0.81 0.13 0.005
Upper arm circumference (cm) 0.31 0.40 0.31 0.40 0.172
 20.8 8.2 20.49 7.80 0.348
 29.4 8.50 28.89 8.10 0.157
 49.3 10.2 49.89 10.55 0.009
 70.62 8.50 71.11 8.10 0.157
Systolic Blood Pressure (mmHg) 120.33 13.26 115.58 13.05 0.012
Diastolic Blood Pressure (mmHg) 80.04 10.49 78.31 7.95 0.196
Plasma glucose (mmol/l) 5.37 0.51 5.31 0.49 0.688
Plasma insulin (mIU/l) 8.24 10.34 6.79 8.06 0.197
Total cholesterol (mmol/l) 4.45 0.73 4.49 0.77 0.654
HDL cholesterol (mmol/l) 1.72 0.29 1.65 0.30 0.085
LDL cholesterol (mmol/l) 2.34 0.72 2.34 0.77 0.940
Triglycerides (mmol/l) 0.90 0.43 1.09 0.60 0.126
HOMA-IR 2.22 2.62 1.61 1.88 0.045
Uric acid (mmol/l) 0.278 0.13 0.268 0.13 0.525
 0.516 0.21 0.395 0.11 0.057
Table 2: 

Baseline (week 0) Post intervention (week 4) P value
Mean SD Mean SD
 72.01 12.05 71.79 12.29 0.616
BMI (kg/m2) 24.77 3.43 24.64 3.54 0.359
 0.816 0.09 0.798 0.10 0.004
Upper arm circumference (cm) 0.312 0.028 0.312 0.032 0.939
 20.69 7.18 19.96 7.34 0.078
 28.69 7.78 27.69 7.63 0.038
 51.32 10.85 51.84 10.50 0.133
 71.31 7.77 72.31 7.63 0.038

Effect of Pomegranate Extract Consumption on Cardiovascular Disease Risk Factors, Stress Hormones, and Qual-
ity of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial
403
Citation:
Angela Stockton., et al-
mones, and Quality of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial”. EC Nutrition
2.4 (2015): 396-411.
Systolic Blood Pressure (mmHg) 111.55 11.86 112.26 7.95 0.798
Diastolic Blood Pressure (mmHg) 79.98 5.71 77.64 5.49 0.114
Plasma glucose (mmol/l) 5.08 0.37 5.09 0.32 0.841
Plasma insulin (mIU/l) 10.92 8.26 7.65 5.79 0.078
Total cholesterol (mmol/l) 4.33 0.68 4.33 0.81 0.979
HDL cholesterol (mmol/l) 1.58 0.29 1.58 0.25 0.922
LDL cholesterol (mmol/l) 2.28 0.52 2.32 0.53 0.782
Triglycerides (mmol/l) 1.02 0.35 0.95 0.66 0.584
HOMA-IR 2.44 1.79 1.70 1.26 0.072
Uric acid (mmol/l) 0.24 0.05 0.27 0.05 0.067
 0.37 0.14 0.45 0.17 0.048
Table 3: 

Effect on Stress Hormones

  
      
 

Figure 3a:

**p = 0.001, * p = 0.01.

Effect of Pomegranate Extract Consumption on Cardiovascular Disease Risk Factors, Stress Hormones, and Qual-
ity of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial
404
Citation:
Angela Stockton., et al-
mones, and Quality of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial”. EC Nutrition
2.4 (2015): 396-411.
Figure 3b:

Figure 4a:


Effect of Pomegranate Extract Consumption on Cardiovascular Disease Risk Factors, Stress Hormones, and Qual-
ity of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial
405
Citation:
Angela Stockton., et al-
mones, and Quality of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial”. EC Nutrition
2.4 (2015): 396-411.
Effect on blood pressure, insulin and insulin resistance (HOMA-IR)
  



the study.
Figure 4b:

Figure 5:
Effect of pomegranate capsule and placebo on systolic and diastolic blood pressure. There was



Effect of Pomegranate Extract Consumption on Cardiovascular Disease Risk Factors, Stress Hormones, and Qual-
ity of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial
406
Citation:
Angela Stockton., et al-
mones, and Quality of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial”. EC Nutrition
2.4 (2015): 396-411.
Figure 6: Effect of pomegranante capsules consumption on homeostasis model assessment of insulin-resistance


Effect on blood lipids
Effect on health related quality of life
Discussion

group, total cholesterol and LDL cholesterol were similar at baseline and at 4 weeks and a slight decrease was found in HDL cholesterol




-
cal functioning (p = 0.018), social functioning (p = 0.021), pain (p = 0.003), general health (p = 0.008) and overall rand score (p = 0.007).

 -
ences between the placebo and PE groups at baseline.
                 

-
 
variety of CVD risk factors.

Effect of Pomegranate Extract Consumption on Cardiovascular Disease Risk Factors, Stress Hormones, and Qual-
ity of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial
407
Citation:
Angela Stockton., et al-
mones, and Quality of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial”. EC Nutrition
2.4 (2015): 396-411.



-

  

-



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
PE consumption has improved insulin resistance in our participants. Physiologically, cortisol is essential for the maintenance of blood




  -



 


Placebo Pomegranate Extract (PE)
Basal 4 weeks p-value Basal 4 weeks p-value
Physical functioning 94.29 (6.16) 96.07 (6.56) 0.292 92.33 (8.84) 98.00 (3.68) 0.018
Role limitations due to physical health 80.36 (36.92) 87.50 (32.15) 0.537 90.00 (28.03) 94.17 (14.07) 0.565
Role limitations due to emotional problems 76.19 (42.22) 88.10 (21.11) 0.239 70.01 (30.99) 77.23 (33.40) 0.216
 58.57 (16.34) 58.57 (13.51) 1.000 53.33 (14.10) 60.00 (16.70) 0.131
Emotional well being 69.14 (16.93) 76.93 (10.72) 0.016 65.33 (13.91) 70.93 (14.46) 0.146
Social functioning 78.57 (23.22) 89.29 (12.84) 0.139 80.83 (14.07) 92.50 (12.32) 0.021
Pain 73.39 (23.24) 82.68 (15.30) 0.147 76.67 (16.92) 89.18 (8.57) 0.003
 71.43 (12.62) 73.21 (13.39) 0.572 64.33 (17.10) 71.00 (16.17) 0.008
Overall Rand 75.25 (14.61) 81.56 (7.93) 0.091 74.12 (10.70) 81.63 (11.08) 0.007
Table 4: 


Effect of Pomegranate Extract Consumption on Cardiovascular Disease Risk Factors, Stress Hormones, and Qual-
ity of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial
408
Citation:
Angela Stockton., et al-
mones, and Quality of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial”. EC Nutrition
2.4 (2015): 396-411.
-
-

      
      


The type of polyphenols in pomegranate extract and their combination might have impacted positively on CVD risk measurements.

-

are supported by data from Mena., et alet al
The question of bioavailability of pomegranate polyphenols remains controversial. Some authors have concluded that phenolic
-

    

  
PE on CVD risk factors, stress and quality of life in healthy human volunteers. PE has the potential to provide a convenient, low cost
    
to recruit a large enough sample (approximately n = 30) to provide useful information about the aspects being assessed for feasibility

-

Data collection was by one investigator in one trial centre which assured a high quality of data collected and was likely to impact
positively on the recruitment and retention of participants. The recruitment and retention rates for the study were excellent with one
   -
drawals from the groups after the start of the intervention.
Limitations and strengths of the study
Conclusion
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Effect of Pomegranate Extract Consumption on Cardiovascular Disease Risk Factors, Stress Hormones, and Qual-
ity of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial
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Citation:
Angela Stockton., et al-
mones, and Quality of Life in Human Volunteers: An Exploratory Randomised, Double-Blind, Placebo-Controlled Trial”. EC Nutrition
2.4 (2015): 396-411.
Volume 2 Issue 4 October 2015
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