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Int. J. Med. Sci. 2011, 8
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2011; 8(3):192-197
Research Paper
Effect of Acute Administration of an Herbal Preparation on Blood Pressure
and Heart Rate in Humans
John G. Seifert1, Aaron Nelson2, Julia Devonish2, Edmund R. Burke3, and Sidney J. Stohs4
1. Movement Science/Human Performance Laboratory, Montana State University, Bozeman, MT, USA
2. Human Performance Laboratory, St. Cloud State University, St. Cloud, MN, USA
3. Dept of Biology, Colorado University – Colorado Springs, Colorado Springs, CO, USA
4. School of Pharmacy and Health Professions, Creighton University Medical Center, Omaha, NE, USA
Corresponding author: john.seifert@montana.edu, 406-994-7154
© Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/
licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.
Received: 2010.10.05; Accepted: 2011.01.31; Published: 2011.03.02
Abstract
Confusion and controversy exist regarding the cardiovascular effects of dietary supplements
containing caffeine and Citrus aurantium (bitter orange) extract. The primary protoalkaloidal
ingredient in bitter orange extract is p-synephrine which has some structural similarities to
ephedrine and nor-epinehrine, but exhibits markedly different pharmacokinetic and receptor
binding properties. The goal of this study was to investigate the cardiovascular effects of a
product containing caffeine, bitter orange extract (p-synephrine) and green tea extract in
mildly overweight individuals. Fourteen female and nine male subjects (age 24.7 +7.4 yrs, BMI:
26.6 +3.8) volunteered in this randomized, placebo-controlled, crossover, double-blind de-
signed study. On day one, subjects entered the laboratory following an overnight fast. Heart
rate and blood pressure were recorded at 60 min. Expired air was analyzed for the next 10
min of the session. At each of three meals, subjects ingested one capsule that was either a
non-caloric placebo or a dietary supplement that contained 13 mg p-synephrine and 176 mg
caffeine. On the following day, the subjects returned and repeated the protocol for data
collection beginning 60 min after consuming one capsule of the placebo or the dietary sup-
plement. No effects of the dietary supplement on heart rate, systolic and diastolic blood
pressure or mean arterial pressure were observed. No between or within group differences
were observed when data were analyzed for gender and caffeine usage. A small but significant
decrease in resting respiratory exchange ratio was observed for the low caffeine user group in
response to the product containing caffeine and p-synephrine. The results of this study in-
dicate that ingestion of a product containing bitter orange extract, caffeine and green tea
extract does not lead to increased cardiovascular stress and that fat oxidation may increase in
certain populations.
Key words: Citrus aurantium, p-synephrine, blood pressure, heart rate, bitter orange, caffeine, green
tea
Introduction
Approximately two-thirds of the adult American
population are overweight while about one-third is by
definition considered to be obese [1]. The increase in
obesity is associated with increased incidences of di-
abetes, hypertension, hyperlipidemias, cardiovascular
diseases, stroke, and premature deaths at a cost of
billions of dollars annually [2, 3]. As a consequence,
great emphasis is being placed on various approaches
Int. J. Med. Sci. 2011, 8
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193
to weight loss and weight management, including
dietary supplements, diets, and exercise programs.
Citrus aurantium (bitter orange) extract and its
primary protoalkaloidal constituent p-synephrine are
widely used in weight loss and weight management
products in combination with caffeine, polyphenolics,
and other constituents [4-7]. These products are de-
signed to promote thermogenesis and increase me-
tabolism, suppress appetite, and/or slow the absorp-
tion of fats and carbohydrates [5].
In spite of their widespread use and the lack of
credible reports regarding adverse effects, contro-
versy has existed regarding the safety of bitter orange
extract and p-synephrine [8-11]. The safety of
p-synephrine is clouded by its structural similarity to
nor-epinephrine in spite of the fact that the pharma-
cokinetics of the two compounds and the receptor
binding specificities are vastly different due to signif-
icant structural differences [5, 12]. Furthermore, there
is a lack of understanding [8, 10] between the phar-
macological properties of p-synephrine (hydroxyl
group on the para position of the benzene ring) which
is found in C. aurantium, and m-synephrine (phe-
nylephrine; with the hydroxyl group on the meta po-
sition) which is used in nasal decongestants and is not
a constituent of C. aurantium.
Because of the known cardiovascular effects of
nor-epinephrine and ephedrine, it has generally been
assumed that consumption of p-synephrine and bitter
orange extract will likewise result in increases in heart
rate and blood pressure [8-11]. The purpose of this
study was to determine the effects of the acute ad-
ministration of a product containing caffeine from
guarana, p-synephrine from C. aurantium and a green
tea polyphenolic extract on heart rate and blood
pressure in mildly overweight human subjects.
Methods
Twenty-three subjects volunteered to participate
in this double blind, placebo controlled cross-over
study. Fourteen subjects were female and nine were
male. Table 1 summarizes the characteristics of these
subjects. The Institutional Review Board approved
this study prior to data collection. All subjects com-
pleted a health history questionnaire and provided
informed consent prior to participation.
An uninvolved individual randomly divided
subjects into two groups, 12 and 11 subjects per
group. The subjects received either the experimental
product in capsule form or a non-caloric placebo in a
cross-over design. Following data collection, a one
week washout period was provided between the two
experimental procedures. Each capsule of the exper-
imental treatment product (Acceleron®) contained C.
aurantium extract (AdvantraZ®, 6% p-synephrine
yielding 13 mg p-synephrine), 176 mg caffeine in the
form of guarana extract, and 55.5 mg of green tea ex-
tract with small amounts of other ingredients (see
Table 2). While on the experimental treatment, each
subject consumed four capsules for a total of 52 mg
p-synephrine and 704 mg caffeine over a 24 hour pe-
riod.
Table 1. Subject characteristics
Age
(yrs)
Height
(m)
Weight
(kg)
BMI
Overall
24.5 ± 7.4
1.74 ± 0.09
81.1 ± 17.1
26.6 ± 3.8
Females
(n=14)
25.4 ± 9.3
1.68 ± 0.07
72.4 ± 11.8
25.5 ± 3.2
Males (n=9)
23.1 ± 2.5
1.82 ± 0.06
94.5 ± 15.7
28.3 ± 4.1
BMI: Body mass index. Each value is the mean + SD.
Table 2. Dietary supplement ingredients per capsule
Ingredient
Amount
Guarana (caffeine)
176 mg
Citrus aurantium (p-synephrine)
13 mg
Green Tea Powder Extract
55.5 mg
Bee Pollen
1 mg
White Willow Bark Powder
1 mg
Panax ginseng Root
2 mg
Garcinia cambogia extract
2 mg
Vanadium
0.15 mcg
On a given treatment, day one was used to col-
lect baseline data. All subjects were instructed to re-
frain from exercise 24 hours before their trial. Dietary
intake was not controlled, but subjects were instruct-
ed to maintain a consistent intake from trial to trial.
Subjects entered the laboratory on the scheduled
morning following an overnight (12 hour) fast. They
sat quietly for 30 min in a comfortable chair in a room
with dim light.
Expired air was collected for 10 min from 20 to
30 min of this session as subjects breathed through a
one-way breathing valve. Expired air was collected in
Douglas bags and contents measured by Ametek
Oxygen and Carbon Dioxide Analyzers (Thermox,
Pittsburgh, PA) while volume was measured using a
Tissot spirometer. Indirect calorimetry was used to
determine oxygen uptake (VO2) and carbon dioxide
production (VCO2). The non-protein respiratory ex-
change ratio (RER) value was calculated from VO2
and VCO2. The RER was used as an index of fat and
carbohydrate oxidation. Heart rate (Polar HR Moni-
Int. J. Med. Sci. 2011, 8
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194
tor, Stamford, CT) and blood pressure (ausculatory
method) were collected at 30 min.
Following baseline data collection, subjects were
given three treatment capsules and instructed to in-
gest one capsule with each meal during that day.
Subjects returned to the laboratory on the following
morning after an overnight fast and were given the
fourth treatment capsule with water. Subjects then sat
quietly for 60 min. The 60 min period was estimated
to give maximal blood levels of the ingredients [11,
13]. Expired air was then collected and analyzed
during the next 10 min of the session. Heart rate and
blood pressure were recorded at the end of expired air
collection, approximately 72-75 min after capsule in-
gestion.
Three analyses of the data were performed using
2 x 2 analysis of variance (ANOVA). For the first data
analysis, treatment and time were the independent
factors using all 23 subjects. The second analysis sep-
arated and analyzed the data according to gender.
The third analysis assessed the data for differences in
high caffeine and low-caffeine users. Fourteen sub-
jects were classified as low caffeine users and nine as
high caffeine users, employing the breakpoint of 150
mg caffeine per day to separate the two groups. Sta-
tistical significance was established at p<0.05. All data
are reported as mean + standard deviation (SD).
Results
All 23 subjects completed the study. Based on
self-report and questionnaire, all subjects ingested the
given capsules on time as noted in the Methods sec-
tion. No adverse treatment effects were observed or
reported by any of the subjects.
Table 3 contains the cardiovascular data from the
entire subject population. No statistical differences
were observed within groups or between groups for
any of the measures. Heart rate, blood pressure, and
metabolic variables were maintained from baseline to
the post-ingestion collection period regardless of
treatment. Three subjects (one male and two females)
were pre-existing hypertensives (systolic blood pres-
sure > 140 mm Hg). Blood pressures for the hyper-
tensive individuals did not change significantly in
response to the dietary supplement.
Table 4 contains data separated by gender. No
significant differences were observed for the de-
pendent variables in the female group. Likewise,
males did not demonstrate significant differences
when the dietary supplement was ingested.
Data separated into high and low caffeine users
are presented in Table 5. As with the previous anal-
yses, no significant differences were observed for
heart rates or blood pressures between the experi-
mental and placebo control groups. However, there
was a small but significant change in RER data for the
low caffeine users relative to both the placebo control
group and the pre-treatment baseline for the low caf-
feine group. After ingestion of dietary supplement the
low caffeine users exhibited a decrease in RER from
0.84 + 0.05 to 0.81 + 0.04.
Effect sizes were calculated for each of the anal-
yses where data were separated by gender (Table 4) or
caffeine consumption (Table 5). The effects based on
number of subjects per group were all below 0.4, in-
dicating low to moderate influence.
Table 3. The effects of supplementation on cardiovascular
and metabolic parameters (n=23)
Treatment
Heart
Rate
(bpm)
Systolic
BP (mm
Hg)
Diastolic
BP (mm
Hg)
MAP
(mm
Hg)
RER
PL pre
62.4
±11.8
119.9
±12.0
77.7 ± 8.9
91.8 ±
9.1
0.85
±0.07
PL post
60.7
±12.5
118.7
±10.2
76.7 ± 7.8
90.7 ±
8.5
0.86
±0.05
DS pre
63.5
±14.2
119.2
±14.3
76.9 ± 8.4
91.0 ±
9.8
0.85
±0.06
DS post
60.9
±12.4
118.9
±11.1
79.2 ± 6.4
92.4 ±
7.3
0.83
±0.07
PL: Placebo; DS: Dietary Supplement; BP: Blood Pressure; MAP:
Mean Arterial Pressure; RER: Respiratory Exchange Ratio. Each
value is the mean +SD.
Table 4. The effect of gender and supplementation on
cardiovascular and metabolic parameters
Treatment
Heart
Rate
(bpm)
Systolic
BP (mm
Hg)
Diastolic
BP (mm
Hg)
MAP
(mm
Hg)
RER
A. Females
(n=14)
PL pre
65.9
±13.2
117.9
±12.6
76.3
±10.5
90.1
±10.4
0.86
±0.08
PL post
65.1
±13.1
117.2
±12.6
76.1 ±8.9
89.8
±9.5
0.85
±0.05
DS pre
70.2
±13.8
112.8
±12.4
74.2 ±8.8
87.1
±9.4
0.84
±0.05
DS post
65.5
±12.4
116.2
±10.3
79.4 ±5.9
91.7
±7.0
0.82
±0.09
B. Males
(n=9)
PL pre
56.9
±6.3
123.0
±11.0
80.0 ±5.2
94.3
±6.4
0.85
±0.05
PL post
53.9
±8.0
120.9
±11.9
77.7 ±6.3
92.1
±7.2
0.86
±0.05
DS pre
53.1
±7.0
128.1
±11.4
91.0 ±6.2
97.1
±7.3
0.85
±0.06
DS post
53.8
±8.8
123.0
±11.6
78.8 ±7.5
93.5
±8.0
0.83
±0.05
PL: Placebo; DS: Dietary Supplement; BP: Blood Pressure; MAP:
Mean Arterial Pressure; RER: Respiratory Exchange Ratio. Each
value is the mean + SD.
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195
Table 5. The effects of caffeine use and supplementation on
physiological responses.
Treatment
Heart
Rate
(bpm)
Systolic
BP (mm
Hg)
Diastolic
BP (mm
Hg)
MAP
(mm
Hg)
RER
A. Low
Caffeine
Users
(n=14)
PL pre
63.4
±11.9
120.6±12.1
79.8 ±9.6
93.4
±9.7
0.84
±0.06
PL post
63.4
±13.1
117.9±12.7
78.1 ±8.2
91.3
±8.9
0.84
±0.04
DS pre
65.8
(15.2
119.4±13.6
77.9 ±9.2
91.8
±10.3
0.84
±0.05
DS post
64.7
(13.7
120.6±11.1
80.6 ±6.3
94.0
±7.3
0.81
±0.04*
B. High
Caffeine
Users
(n=9)
PL pre
60.9
±12.1
118.8 ±12.5
74.6 ±7.0
89.3
±8.1
0.87
±0.09
PL post
56.7
±10.9
119.8 ±12.2
74.7 ±7.2
89.7
±8.3
0.88
±0.06
DS pre
60.0
±12.6
118.9 ±16.2
75.2 ±7.2
89.8
±9.5
0.86
±0.06
DS post
55.0
±7.3
116.1 ±11.1
76.9 ±6.2
90.0
±7.0
0.86
±0.10
*Significantly different from pre-ingestion value and placebo
groups (P<0.05).
PL: Placebo; DS: Dietary Supplement; Heart Rate; BP: Blood Pres-
sure; MAP: Mean Arterial Pressure; RER: Respiratory Exchange
Ratio. Each value is the mean +SD.
Discussion
The results of this study indicate that acute in-
gestion of a dietary supplement containing caffeine,
bitter orange extract (p-synephrine) and green tea
extract did not lead to significant cardiovascular ef-
fects as reflected by blood pressure and heart rate,
regardless of treatment or subject grouping either by
gender or caffeine usage. Subjects in the present study
ingested 39 mg of p-synephrine and 528 mg of caffeine
the day before testing followed by ingestion of an
additional 13 mg p-synephrine and 176 mg caffeine
the next morning after an overnight fast. This protocol
more closely represents typical ingestion regimes of
dietary supplements used for weight loss and weight
management, and is unique as compared to other
studies that involve only a single dose [11, 13-15].
Controversy exists regarding the cardiovascular
effects of C. aurantium extract in combination with
caffeine, and various authors make the assumption
that an increase in heart rate and blood pressure are to
be expected [8, 10, 16-19]. However, a number of
studies that have assessed the cardiovascular effects
of products composed of C. aurantium extract in com-
bination with caffeine and other ingredients have not
observed an increase in blood pressure [6, 7, 11, 19-21]
or heart rate [ 6, 7, 19-21]. The results of the present
study clearly agree with these previous observations.
Haller et al. [11] examined the cardiovascular
effects associated with a single dose of a mul-
ti-component dietary supplement (Xenadrine®) in 10
subjects. The supplement contained 5.5 mg
p-synephrine, 239 mg caffeine, 5.7 mg octopamine and
undisclosed amounts of other ingredients including
catechin polyphenols. The hemodynamic effects of a
single dose of a C. aurantium extract (Advantra Z®)
that contained 46.9 mg p-synephrine were also ex-
amined. The results demonstrated that the dietary
supplement, but not the p-synephrine-containing bit-
ter orange extract, increased both systolic and dias-
tolic blood pressures at two hours post treatment rel-
ative to the control group. No significant effects of
either treatment on heart rate were noted over the first
three hours after ingestion of the products. However,
a significant increase in heart rate over control was
noted at the six hour time point.
This study of Haller et al. [11] is complicated by
the fact that all subjects consumed a meal three hours
after treatment ingestion. After eating, an increase in
heart rate occurred in all three treatment groups. The
increase in heart rate does not coincide with the
pharmacokinetics including blood levels and half–life
of p-synephrine [11, 13], but does coincide with the
thermic effect of food in this study. Given that the
control group responded similarly to the two treat-
ment groups after the meal at the four and eight hour
measurements (one and five hours after the meal), the
reason for the apparently significant difference seen at
only the six hour time point (three hours after the
meal) is unclear. No explanation is given by the au-
thors for this change in heart rate. Gougeon et al. [19]
reported that the thermic effect of food increased by
29% in 17 females after they ingested 26 mg
p-synephrine. The thermic effect of p-synephrine was
greater in males than females in the absence of a meal,
and no significant changes occurred in pulse rates or
blood pressures when compared with baseline values.
Haller et al. [13] have also examined the effects,
under resting and exercise conditions, of a dietary
supplement designed to enhance athletic performance
in 10 subjects. The product (Ripped Fuel Extreme
Cut®) contained 21 mg p-synephrine, 304 mg caffeine,
as well as extracts of green tea, ginger root, cocoa
seed, willow bark and wasabi. The placebo or product
was taken one hour before 30 min of moderately in-
tense exercise. There were no treatment- related dif-
ferences in post-exercise heart rate, systolic blood
pressure or body temperature. A significant prod-
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uct-related increase in diastolic blood pressure (8.7
mm Hg) was observed, apparently counteracting the
vasodilatory effects of exercise. Due to the
poly-herbal, poly-alkaloidal and poly-protoalkaloidal
nature of this product, the ingredient or ingredients
responsible for the observed effect cannot be deter-
mined.
Bui et al. [15] conducted a study on 15 healthy
subjects given a single oral dose of 900 mg bitter or-
ange extract (Nature’s Way) that contained 6 %
p-synephrine (54 mg p-synephrine) or the placebo.
Small but significant increases were observed in heart
rate, and systolic and diastolic blood pressures for up
to five hours. Of interest is the fact that Min et al. [18]
used this same product in a similarly designed study
and saw no effect in 18 subjects on systolic or diastolic
blood pressure, or on the rate-corrected QT (QTc)
interval.
The confusion regarding the purported cardio-
vascular effects of C. aurantium has been due, at least
in part, to a lack of understanding of the differences in
the pharmacokinetic and pharmacological properties
between p-synephrine and m-synephrine (phe-
nylephrine). Failure to differentiate the effects of the
two isomers has resulted in a number of authors at-
tributing the effects of m-synephrine to p-synephrine
[see for example 8, 10, 17, 18, 21]. p-Synephrine (hy-
droxyl group in the para position on the benzene ring)
is the isomeric form found in C. aurantium (bitter or-
ange). m-Synephrine (hydroxyl group in the meta
position) is not a constituent of bitter orange nor is it
present in standardized C. aurantium reference mate-
rials [22]. The m-synephrine (phenylephrine) is read-
ily available as an over-the-counter nasal decongest-
ant, is also used as an ophthalmic product for mydri-
asis, and is known for its cardiovascular effects [23].
The differences in pharmacological properties of
the m- and p- isomers of synephrine can be explained
on the basis of adrenergic receptor binding. It is well
known that, in general, binding to α-adrenergic re-
ceptors results in vasoconstriction, with increased
cardiovascular contractility and increased heart rate
occurring in response to β1-adrenergic receptor
binding, while bronchodilation occurs in response to
β2-adrenergic receptor binding [24]. Activation of
β3-adrenoreceptors is believed to be associated with
lipolysis and thermogenesis, and not adverse cardio-
vascular effects [25]. The belief that p-synephrine ex-
erts its effects by binding primarily to this receptor is
supported by experimental [26] and receptor binding
studies [27].
The cardiovascular effects of caffeine are known
to depend on the extent of regular exposure [28, 29].
Caffeine–naïve subjects can experience an increase in
blood pressure and heart rate, while regular users of
caffeine-containing products develop a tolerance to
these effects. In this study, even the low caffeine users
did not demonstrate an increase in these cardiovas-
cular effects. The observation that the low caffeine
intake group showed a reduction in RER may be a
reflection of caffeine sensitivity. Caffeine is known to
increase fat oxidation (lower RER), and this group
may have been more responsive to the caffeine in the
product.
Although the number of subjects used in this
study is not large (n=23), this number exceeds the
number of subjects used in frequently referenced
studies involving bitter orange extract. For example,
Haller et al. [11, 13] used 10 subjects in each study,
while Sale et al.[20] used 20 subjects, Bui et al. [15]
used 15 subjects and Min et al. [14] used 18 subjects.
Furthermore, as noted in the results, because of the
small numbers of subjects when the data were sepa-
rated based on gender and caffeine intake, size effects
were calculated for each of these analyses. The effects
of size were low (0.2) for gender and moderate (0.4)
for the low caffeine users with respect to RER.
In summary, the results of this study indicate
that ingestion of a product containing bitter orange
extract (p-synephrine), caffeine and green tea extract
in a short-term dosing schedule similar to that com-
monly used with dietary supplements did not result
in alterations in heart rate or blood pressure. Howev-
er, longer term studies are required to assess these
effects under conditions similar to those encountered
when using the product in conjunction with a long
term weight loss program.
Acknowledgements
The authors would like to thank the subjects for
their cooperation. This study was funded by a grant
from Enforma Natural Products. This article is dedi-
cated to Dr. Ed Burke, who passed away before the
completion of this paper.
Conflict of Interest
The authors have declared that no conflict of in-
terest exists.
References
1. Flegal KM, Carroll MD, Ogden CL, et al. Prevalence and trends
in obesity among US adults, 1999-2008. J Amer Med Assoc.
2010; 303(3): 235-241.
2. Lubitz CL, Flegal KM, Pamuk ER. The predicted effects of
chronic obesity in middle age on medicare costs and mortality.
Med Care. 2010; 48(6): 510-517.
3. Barkin SL, Heerman WJ, Warren MD, et al. Millennials and the
world of work: the impact of obesity on health and productiv-
ity. J Bus Psychol. 2010; 25(2): 239-245.
Int. J. Med. Sci. 2011, 8
http://www.medsci.org
197
4. Preuss HG, DiFerdinando D, Bagchi M, et al. Citrus aurantium
as a thermogenic, weight-reduction replacement for ephedra:
an overview. J Med. 2002; 33: 247-264.
5. Stohs SJ, Shara M. A review of the safety and efficacy of Citrus
aurantium in weight management. In: Bagchi D and Preuss HG,
editors. Obesity: epidemiology, pathophysiology, and preven-
tion. Boca Raton (FL): CRC Press; 2007: 371-382.
6. Colker CM, Kalman DS, Torina GC, et al. Effects of Citrus au-
rantium extract, caffeine and St. John’s wort on body fat loss,
lipid levels and mood states in normal weight and obese indi-
viduals. Curr Therap Res. 1999; 60: 145-153.
7. Zenk JL, Leikam SA, Kassen LJ, et al. Effect of Lean System 7 on
metabolic rate and body composition. Nutrition 2005; 21:
179-185.
8. Bent S, Padula A, Neuhaus J. Safety and efficacy of citrus au-
rantium for weight loss. Am J Cardiol. 2004; 94:1359-1361.
9. Fugh-Berman A, Myers A. Citrus aurantium, an ingredient of
dietary supplements marketed for weight loss: current status of
clinical and basic research. Exp Biol Med. 2004; 229:698-704.
10. Penzak SR, Jann MW, Cold JA, et al. Seville (sour) orange juice:
synephrine content and cardiovascular effects in normotensive
adults. J Clin Pharmacol. 2001; 41:1059-1063.
11. Haller CA, Benowitz NL, Jacob IIIP. Hemodynamic effects of
ephedra-free weight-loss supplements in humans. Am J Med.
2005; 118:998-1003.
12. Stohs SJ, Preuss HG. The Safety of bitter orange (Citrus au-
rantium) and its primary alkaloid p-synephrine. HerbalGram
2011; 89: 34-39.
13. Haller CA, Duan M, Peyton J III, et al. Human pharmacology of
a performance-enhancing dietary supplement under resting
and exercise conditions. Brit J Clin Pharmacol. 2008; 65: 833-840.
14. Min B, Cios D, Kluger J, et al. Absence of
QTc-interval-prolonging or hemodynamic effects of a single
dose of bitter orange extract in healthy subjects. Pharma-
cotherapy. 2005; 25: 1719-1724.
15. Bui LT, Nguyen DT, Ambrose PJ. Blood pressure and heart rate
effects following a single dose of bitter orange. Ann Pharma-
codyn. 2006; 40: 53-57.
16. Gray S, Woolf AD. Citrus aurantium used for weight loss by an
adolescent with anorexia nervosa. J Adol Hlth. 2005; 37:
415-416.
17. Thomas JE, Munir JA, McIntyre PZ, et al. STEMI in a
24-year-old man after use of a synephrine-containing dietary
supplement. A case report and review of the literature. Texas
Heart Inst J. 2009; 36: 586-590.
18. Stephensen TA, Sarlay Jr R. Ventricular fibrillation associated
with use of synephrine containing dietary supplement. Military
Med. 2009; 174:1313-1319.
19. Gougeon R, Harrigan K, Tremblay JF, et al. Increase in the
thermic effect of food in women by adrenergic amines extracted
from citrus aurantium. Obesity Res. 2005; 13: 1187-1194.
20. Sale C, Harris RC, Delves S, et al. Metabolic and physiological
effects of ingesting extracts of bitter orange, green.tea and
guarana at rest and during treadmill walking in overweight
males. Int J Obesity 2006; 30: 764-773
21. Smedema JP, Muller GJ. Coronary spasm and thrombosis in a
bodybuilder using a nutritional supplement containing
synephrine, octopamine, tyramine and caffeine. So African Med
J. 2008; 98: 372-373.
22. Sander LC, Putzbach K, Nelson BC, et al. Certification of
standard reference materials containing bitter orange. Analyt
Bioanalyt Chem. 2008; 391: 2023-2034.
23. Stewart A, Fernando R, McDonald S, et al. The dose-dependent
effects of phenylephrine for elective cesarean delivery under
spinal anesthesia. Anesth Analg. 2010 [epub ahead of print].
24. Inchiosa MAJr. “Evidence (mostly negative) with the use of
sympathomimetic agents for weight loss”. J Obesity 2011 [epub
ahead of print].
25. Arch JR. β-3-Adrenoreceptor agonists: potential, pitfalls and
progress. Eur J Pharmacol. 2002; 440: 99-107.
26. TsujitaT, Takaku T. Lipolysis induced by segment wall extract
from Satsuma mandarin orange (Citrus unshu Mark). J Nutr Sci
Vitaminol. 2007; 53: 547-551.
27. Carpene C, Galitzky J, Fontana E, et al. Selective activation of
beta 3-adrenoreceptors by octopamine: comparative studies in
mammalian fat cells. Naunyn Schmiedebergs Arch Pharmacol.
1999; 359: 310-321.
28. Dews PB. Caffeine. Ann Rev Nutr. 1982; 2: 323-341.
29. Dews PB, O’Brien CP, Bergman J. Caffeine: behavioral effects of
withdrawal and related issues. Food Chem Tox. 2003; 40:
1257-1261.
