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 .