the bioflavonoids hesperetin and naringenin are widely distributed in citrus fruits and juices as their glycosides , hesperidin and naringin , respectively .
they are present in citrus aurantium as well as a wide variety of other citrus species 1 .
the sugar moieties for both flavonoids consist of rhamnose plus glucose , which must be removed in the intestinal tract before the flavonoids can be absorbed 2 , 3 .
the absorption of these flavonoids in human subjects has been extensively studied and depends in part upon the forms in which they are ingested ( juice or fruit , glycoside or aglycone , capsule , tablet , etc . ) 4 - 8 .
experiments involving human subjects , animals and cell culture systems have shown that the two flavonoids exhibit a wide range of potentially beneficial physiological and biochemical effects .
naringen and/or hesperidin or their aglycones have been shown to improve insulin sensitivity and glucose tolerance 9 , prevent accumulation of triglycerides 9 , inhibit cholesterol biosynthesis 10 , 11 , and serve as antioxidants and anti - inflammatory agents 12 , 13 as well as hepatoprotectants 14 and neuroprotectants 15 .
however , the effects of naringin and hesperidin on metabolic rate and energy utilization have not been previously assessed .
studies have suggested that p - synephrine has thermogenic and lipolytic activities 16 - 18 , increasing energy metabolism 19 , 20 as well as athletic performance 21 .
p - synephrine is the primary protoalkaloid in bitter orange extract which is derived from the immature fruits of citrus aurantium 22 - 25 , and is widely distributed in other citrus species 22 , 23 , 26 .
the safety of p - synephrine and bitter orange extract has recently been reviewed 27 , and based on the available studies in animals , humans and cell culture systems , it has been concluded that when taken orally and in recommended amounts both are safe .
p - synephrine is widely used in combination with caffeine and other ingredients in products designed to support weight management 19 , 28 .
however , no studies have been reported comparing the thermogenic effects of p - synephrine when combined with the flavonoids hesperidin and naringin .
this pilot study was designed to examine these effects using a comparative effectiveness research ( cer ) study design 29 in a double - blinded , randomized , placebo - controlled protocol to compare the effects of p - synephrine alone and in combination with different amounts of hesperidin and naringin on : ( 1 ) resting metabolism , ( 2 ) blood pressure , ( 3 ) resting heart - rate , and ( 4 ) self - reported mood / energy levels in healthy human subjects .
a total of 50 participants gave written informed consent in compliance with the helsinki declaration and approved by integrative health technologies ' ethics committee .
participants fasted for 8 - 10 hours without consuming caffeinated beverages , nicotine , exercising or participating in vigorous physical activities . upon reporting to the research center
after remaining seated in an isolated area for 10 - 15 min . , participants completed measurements of their blood pressure , resting heart - rate and resting metabolism using micro life 's medgem indirect calorimeter ( microlife medical home solutions , golden , co. 80401 ) .
the medgem is a hand - held , self - calibrating calorimeter that measures oxygen consumption ( vo2 ) to determine resting metabolic rate ( rmr ) . in conjunction with the study , test - retest reliabilities of the instrument
were measured on 41 subjects from test - retest periods ranging from 1 - 17 days between tests .
the average reliability coefficient was 90.2 % , a coefficient that was consistent over the four test - retest periods .
p - synephrine was administered in the form of the patented bitter orange extract advantra zwhich contained 60 % of this active material .
subsequent to rmr measurements , participants were randomly assigned to one of the five double - blinded treatment conditions in which they consumed one ounce of v-8 juice containing the following ingredient variations : group 1 : placebo ( v-8 juice only ) group 2 : advantra z ( 50 mg of p - synephrine ) group 3 : advantra z with 0 mg hesperidin and 600 mg naringin group 4 : advantra z with 100 mg hesperidin and 600 mg naringin group 5 : advantra z with 1,000 mg hesperidin and 600 mg naringin after remaining seated and resting for 45 min .
after 75 min . , a third and final self report rating scale was completed , and measurements of blood pressure , heart - rate and rmr were determined .
anovas were calculated between the groups ' baseline , ending and change scores for each treatment group in addition to dunnett 's t - test between each of the treatment groups and the placebo group .
anovas were calculated between the groups ' baseline , ending and change scores for each treatment group in addition to dunnett 's t - test between each of the treatment groups and the placebo group .
figure 1 shows the changes in resting metabolic rates ( rmrs ) from baseline expressed as kcals for each of the treatment groups ( n=10 per group ) . as expected , a small decrease occurred in the rmr of the placebo group since these participants continued their 8 - 10 hour fast ( group1 ) .
as compared to placebo , 50 mg p - synephrine ( advantra z ) alone ( group 2 ) more than doubled consumption by 65 kcals over placebo . in group 3 , adding 600 mg naringin to the 50 mg p - synephrine further increased calorie consumption more than three - fold to 122 kcals over placebo .
the addition of 100 mg hesperidin to the p - synephrine plus naringin in group 4 resulted in a further increase in calorie consumption by 5-fold to 183 kcal over placebo .
however , in group 5 , when the amount of hesperidin consumed in conjunction with the 50 mg p - synephrine plus 600 mg naringin was increased to 1000 mg , the increase in calorie consumption over placebo was only 79 kcal , an increase between calorie consumption in the absence of hesperidin and in the presence of 100 mg hesperidin . in spite of the low levels of statistical power in these groups of only 10 subjects ,
the increases in rmr in group 4 was significantly greater than placebo ( p=0.039 ) and advantra z alone ( group 2 ) .
it is also worth noting the a repeated - measures students ' t - test revealed that the changes from baseline in group 3 and group 4 were both statistically significant ( p=0.001 and 0.030 , respectively ) .
table 2 shows changes in blood pressures and resting heart - rates from baseline to the ending test for each of the five study groups .
the average baseline blood pressures and resting heart - rates for the study cohort were well within the normal ranges of 121/74 mm hg and 70 bpm .
at the conclusion of the study ( 75 min . ) , no increases in either systolic or diastolic blood pressures or heart rate were observed .
none of the baseline - ending changes approached statistical significance nor were there any statistically significant differences between any of the five study groups .
table 3 depicts the results of the self - report ratings for the 10 symptoms .
as compared to the placebo group , none of the changes in these 10 self - reported symptoms were statistically significant either 45 or 75 min . from baseline .
no significant effects relative to the placebo group were observed by the participants in the four treatment groups for symptoms including anxiety , hunger , tension , sleepiness , energy , nervousness , headache , upset stomach , concentration or general discomfort .
using a double - blinded , randomized , placebo - controlled protocol , this study compared the effects of 50 mg p - synephrine ( as advantra z ) alone with three different amounts of hesperidin and naringin on : ( 1 ) resting metabolism rate , ( 2 ) blood pressure , ( 3 ) resting heart - rate , and ( 4 ) self - reported mood / energy levels in healthy human subjects .
test - retest period since subjects continued the 8 - 10 hour fast they began prior to the start of the study ( figure 1 ) .
the addition of p - synephrine , hesperidin , and naringin led to increases in rmr over placebo .
however , while adding 100 mg of hesperidin in group 4 led to an increase in rmr over placebo , an unexpected reduction was observed in the rmr in group 5 which received 1000 mg hesperidin as compared to group 4 .
these data indicate that increasing the hesperidin from 100 mg to 1,000 mg reversed some of the thermogenic effects of 100 mg hesperidin in combination with 50 mg p - synephrine plus 600 mg naringin
. it may be that in this case , more is not better , and increasing the amount of hesperidin constitutes an example of hormesis 30 , 31 .
the increase in the metabolic rate between p - synephrine alone and the placebo control was approximately 6.9 % .
this increase in thermogenesis is similar to the increases reported in previous studies involving p - synephrine 17 , 18 .
the increase in rmr between group 4 , the combination of p - synephrine with 600 mg naringin and 100 mg hesperidin , and the placebo control is approximately 17.7 % .
if one assumes that the product was taken twice a day for one year , the theoretical increase in calorie consumption would amount to over 31 pounds .
however , the actual extent of weight loss if the product was consumed under these conditions remains to be determined .
the mechanism by which naringin and hesperidin increase the thermogenic effect of p - synephrine may involve enhancing the expression of adiponectin which is known to play a role in lipid and glucose metabolism .
32 have shown that naringenin and hesperetin up - regulate adiponectin expression , and both activate the peroxisome proliferator - activated receptor- ( ppar ) which has been recognized as the master regulator of adipocyte differentiation .
in addition , naringenin also possessed significant ability to activate ppar 32 , a major regulator of lipid metabolism in the liver .
products with thermogenic properties are frequently associated with elevated blood pressures and heart - rates .
p - synephrine is a phenylethylamine derivative with some structural similarities to ephedrine , and is thus assumed to exert cardiovascular effects by many authors [ see for example , 20 , 21 , 33 - 35 ] .
however , no effects on heart rate or blood pressure were observed in response to p - synephrine or p - synephrine in combination with naringin and hesperidin ( table 2 ) .
p - synephrine differs from ephedrine in that it has a hydroxyl group on the para position of the benzene ring and lacks the methyl group on the side chain of the molecule .
these structural differences greatly alter the pharmacokinetic and receptor binding properties of p - synephrine , resulting in little or no cardiovascular effects 27 , as confirmed by this study .
no adverse events have been directly attributable to bitter orange extract and p - synephrine 36 , 37 . however , caffeine is commonly present in products that contain p - synephrine 19 , 28 , and is well known to produce cardiovascular effects 38 , particularly in caffeine - sensitive individuals 39 .
the absence of changes in blood pressure , resting heart - rate and self - ratings in the four treatment groups involving p - synephrine , naringin and hesperidin relative to the placebo group is very positive , and in conjunction with the increased thermogenesis may result in the development of beneficial products with respect to weight loss and weight management .
the findings were further substantiated by consistency of the results across all four treatment groups . however , longer term studies are required to assess the amount of weight that is actually lost in response to these products , and to provide information concerning safety when used over an extended period of time .
a problem faced in studies of thermogenic effects is that noticeable changes in the mood states listed in table 1 often make subjects aware of whether or not they are receiving a placebo , thus undermining blinding of the study .
the lack of significant differences between the treatment groups and the control group with respect to the self - report ratings of symptoms increases confidence in the safety of the combination as well as in the blinding procedure used in this study
. strengths of the study are the use of randomized placebo - controlled double - blinded study design , the absence of thermogenic changes in the placebo group , the absence of adverse effects on blood pressure , heart - rate and self - reports in the four treatment groups , the consistency of the effects of p - synephrine on metabolism in all treatment groups , and the increases in rmr in the treatment groups .
the weakness of this study is the small number ( 10 ) of subjects in the placebo and in each of the treatment groups .
the study also reveals an interesting effect with respect to hesperidin where an increased amount may lead to a masking of the thermogenic effects found with lesser amounts .
this randomized double - blinded placebo control pilot study supports the safety and thermogenic effects of p - synephrine , particularly when combined with 600 mg of naringin and 100 mg of hesperidin .
no increase in heart rate or blood pressure was observed over the 75 min . of the study nor were there any differences in a self - reported rating of 10 common symptoms between the treated and placebo groups .
the data suggests the combination of the flavonoids naringin and hesperidin with p - synephrine may assist weight management .
further studies are required to determine optimal doses as well as safety and efficacy associated with long term use .
 bitter orange ( citrus aurantium ) extract is widely used in dietary supplements for weight management and sports performance . 
 its primary protoalkaloid is p - synephrine . 
 most studies involving bitter orange extract and p - synephrine have used products with multiple ingredients . 
 the current study assessed the thermogenic effects of p - synephrine alone and in conjunction with the flavonoids naringin and hesperidin in a double - blinded , randomized , placebo - controlled protocol with 10 subjects per treatment group . resting metabolic rates ( rmr ) , blood pressure , heart rates and a self - reported rating scale 
 were determined at baseline and 75 min after oral ingestion of the test products in v-8 juice . 
 a decrease of 30 kcal occurred in the placebo control relative to baseline . 
 the group receiving p - synephrine ( 50 mg ) alone exhibited a 65 kcal increase in rmr as compared to the placebo group . 
 the consumption of 600 mg naringin with 50 mg p - synephrine resulted in a 129 kcal increase in rmr relative to the placebo group . in the group receiving 100 mg hesperidin in addition to the 50 mg p - synephrine plus 600 mg naringin , 
 the rmr increased by 183 kcal , an increase that was statistically significant with respect to the placebo control ( p<0.02 ) . however , consuming 1000 mg hesperidin with 50 mg p - synephrine plus 600 mg naringin resulted in a rmr that was only 79 kcal greater than the placebo group . 
 none of the treatment groups exhibited changes in heart rate or blood pressure relative to the control group , nor there were no differences in self - reported ratings of 10 symptoms between the treatment groups and the control group . 
 this unusual finding of a thermogenic combination of ingredients that elevated metabolic rates without corresponding elevations in blood pressure and heart - rates warrants longer term studies to assess its value as a weight control agent . 
Introduction
Material and methods
Statistical Analyses
Results
Discussion
Conclusions