Bitter Orange

In by Raphikammer


Citrus aurantium (C. aurantium) is the Latin name for a

plant commonly referred to as bitter orange, sour orange,

Neroli, Chongcao, or Seville orange. It is a source

of synephrine and several other biogenic amines, as well

as other bioactive phytochemicals and has been used in dietary

supplements for weight loss. In this entry,we discuss

the available evidence pertaining to safety and efficacy of

C. aurantium for weight loss, as examined in animal studies,

clinical trials, and case reports.


Bitter orange is a member of the Rutaceae family, a hybrid

between Pummelo, Citrus grandis, and Mandarin, Citrus


Native to Asia, various parts of the plant are

used throughout the world for a variety of indications.

Bitter orange and its components are commercially available

in herbal weight loss supplements, ostensibly for their

adrenergic agonistic properties (1), often in combination

with other ingredients hypothesized to promote weight

loss. Its constituent p-octopamine and synephrine alkaloids

(SAs) are usually cited as the active ingredients in

such products (2). With the banning of ephedra in the

United States in 2004, bitter orange has been increasingly

included in weight loss supplement formulations. Because

of similarities in their constituents and possible mechanisms

(both sources of natural alkaloids with sympathomimetic

activity), concerns have been raised that bitter

orange may carry risks similar to those hypothesized to

exist for ephedra (3).


Bitter Orange origin is in China and appears in writing

as far back as 300 BC.

Its ancient use has also been documented

in Japan and Rome (4). It is native to eastern

Africa, Arabia, and Syria and is cultivated in various European,

North American, and South American regions. The

leaf was historically used as a tonic, laxative, or sedative

in Mexico and South America and for insomnia, palpitations,

or stomachaches by the European Basque people

(5,6). The fruit and peel are also used for stomach aches, as

well as high blood pressure (BP), spasm, and a variety of

gastrointestinal conditions by both the Basque and practitioners

of traditional Chinese medicine (7). While the

practice arose in Ancient Egypt, neroli oil is still currently

used for aromatherapy and bergamot, a subspecies of

C. aurantium, is used for flavoring and aroma in Earl Grey

teas (8). Modern uses for C. aurantium include digestive,

cardiovascular, neuromuscular, and antiseptic indications

in countries such as China, Curacao, Haiti, India, Mexico,

Trinidad, Turkey, and the United States (9). The most

common current western use, however, is as a dietary

supplement for weight loss.


Some authors (10) state that C. aurantium contains meta synephrine

(m-synephrine, m-s), whereas others (11) state

that it contains only para-synephrine (p-synephrine, ps).

However, research (I.A. Khan, oral communication,

2005) has shown that C. aurantium naturally contains

p-synephrine and does not contain m-synephrine. Allison

and colleagues reported that at least one over-the counter

(OTC) product purportedly containing SAs from

C. aurantium contains both p-synephrine andm-synephrine

(12), raising concerns about possible adulteration and

mislabeling. There is also an ortho isomer of synephrine

(o-synephrine), whose content in C. aurantium is unknown.

p-, m-, and o-synephrine can each exist in D or L forms.

p-Synephrine, an undisputed component of C. aurantium,

is typically referred to simply as synephrine (13).

It is an -adrenergic agonist (14) that also has some –

adrenergic properties (15). p-Synephrine occurs naturally

in the human body in small quantities and might act as

a neurotransmitter (16). Under the name oxedrine, it has

been used since 1927 (17) in eyedrops. p-Synephrine is

thought to be the ingredient in C. aurantium primarily

responsible for weight loss. However, neither this nor

whether C. aurantium actually produces weight loss in

humans is firmly established.

m-Synephrine, often referred to as phenylephrine,

is an isomer of p-synephrine. To the best of our knowledge,

m-synephrine is not contained naturally in C. aurantium.

m-Synephrine is also an -adrenergic agonist that has

some -adrenergic agonist properties. It has been studied

more extensively than p-synephrine and is one of the

two most widely used OTC decongestants today (Fig. 1)

(13). p-Synephrine and m-synephrine have similar structure

to ephedrine, as well as other substances that have

some effects on reducing food intake and/or body weight

such as epinephrine and norepinephrine (Fig. 1), supporting

the conjecture that, to the extent that function follows

structure, p-synephrine and m-synephrine, may also reduce

food intake and or body weight.

The -adrenergic sympathomimetic amine, octopamine,

is also present in C. aurantium, though possibly

at appreciable levels (2). Like both forms of

synephrine, it is an -adrenergic agonist with some

Chemical structures of (A) p-synephrine, (B) m-synephrine,

(C) ephedrine, (D) epinephrine, and (E) norepinephrine.

-adrenergic properties. It is used to treat hypertension

and as a cardiotonic (13) and has also been examined for

its potential role in promoting weight loss (18).

Because of their similar properties and the overlap

of their inclusion in supplements, we will refer to these

substances collectively as synephrine alkaloids (SAs). SAs

are used clinically as decongestants (1), during surgical

procedures as a vasopressor (19), for acute treatment of

priapism (20), and in ophthalmological examinations for

pupil dilation (21). Products that contain C. aurantium or

its derivatives, including OTC weight loss supplements,

will be referred to as C. aurantium products (CAPs).

Regulatory oversight for dietary supplements is

much less rigorous than for pharmaceuticals, and extensive

evidence is not required prior to release of a product

on the public market. While a phase of requirements for

meeting good manufacturing practices is currently underway,

this may help to explain why the quality and quantity

of the evidence we have available to evaluate the safety

and efficacy of C. aurantium is minimal.


As sympathomimetic agents with both – and –

adrenergic receptor agonist properties, SAs might increase

energy expenditure and/or decrease food intake (22). In

addition, there is some evidence that adrenergic agonists,

including SAs, decrease gastric motility (23). Similar to

compounds such as cholecystokinin and other gut peptides

which both decrease gastric motility and food intake

(24), one might conjecture that SAs may also decrease food

intake via reducing gut motility. Activation of lipolysis is

a known -adrenergic activity (25) that may be fueled by

these components of C. aurantium.


Bitter Orange Weight Loss

SAs reduce food intake in rodents (26), and some studies

indicate that SAs can reduce rodent body weight

(13,26). SAs have also been shown to promote lipolysis

in adipocytes through -adrenergic stimulation (27)

and to increase lipoprotein lipase activity in the parametrial

fat pad of female hamsters (28). However, among

monosodium glutamate–treated obese mice, SAs reduced

weight gain but had no effect on body fat percent (29).

Toxicity and Mortality

Data suggest that m-synephrine (not present in bitter orange)

may prolong life in rodents. A 2-year study by the

National Toxicology Program (13) evaluated the effects

of m-synephrine on spontaneous food intake of rats and

mice. At 2 years, there were no significant differences in

survival among mice or female rats. However, for male

rats, there was a significant reduction in mortality rate,

although there was increased mortality in the early phase

of the study at the highest dose. It should be noted that

too few deaths occurred during the 2-year trial to provide

the degree of precision and power desired for a rigorous

longevity study (30). Nonetheless, similar results have

been reported for ephedrine, another sympathomimetic

amine (31).

Arbo et al. (32) conducted a subchronic toxicity

study in mice and the effects of p-synephrine and C. aurantium

L. extract on oxidative stress biomarkers that are

believed to be indicators of cell membrane injury (malondialdehyde)

and (glutathione and the enzyme glutathione

peroxidase) indicative of amphetamine-induced toxicity.

The study evaluated adult male CF1 mice treated with

400, 2000, or 4000 mg/kg C. aurantium dried extract and

p-synephrine 30 or 300 mg/kg over the course of 28 days.

Results showed a reduction in glutathione in mice treated

with C. aurantium 400 mg/kg and p-synephrine 30 and

300 mg/kg. Inhibition of glutathione peroxidase activity

occurred within mice treated with C. aurantium 400 and

2000 mg/kg and p-synephrine 30 and 300 mg/kg; however,

no change occurred within malondialdehyde levels.

These two findings suggest the possibility of subchronic

toxicity. No significant change in weight occurred in any

of the groups, suggesting on the positive side a lack of

severe toxicity, and on the negative side a lack of efficacy

in producing weight loss.

With regard to adverse effects, a study (33) of male

Sprague-Dawley rats reported what was believed to be

evidence of cardiotoxicity when C. aurantium fruit extracts

standardized to 4% and 6% SAs were administered. Increased

mortality has been observed among CAPs-treated

rats (33) as well as a strain of mice selected to be uniquely

susceptible to the effects of adrenergic stimulation (34).

CLINICAL TRIALS Bitter Orange Weight Loss

Few clinical trials have examined the effects of CAPs alone

or in combination with other ingredients on body weight

and/or body composition (Table 1). It should be kept in

mind that these trials are of short duration and the sample

sizes are frequently quite small. Nonetheless, these

trials suggest that body weight and/or fat loss may be

enhanced by CAPs or SAs. The mechanisms involved are

unclear but may be partially due to a suppressing effect

of appetite and/or a moderate increase in resting energy


Armstrong et al. (37) evaluated exercise and herbal

preparation containing Ma Huang, bitter orange (5 mg

SAs), and guarana over 6 weeks in a randomized, controlled

trial. Compared with controls, the intervention

group obtained significant reductions in fat mass and a

nearly significant reduction in body mass index (kg/m2)

54 Haaz et al.

Table 1 Summary of Clinical Weight Loss Trials

Reference Treatment Design Sample size Duration Results Comments

Colker et al. (10) 975 mg Citrus

aurantium, +528

caffeine and 900 mg

St. John’s wort;

placebo (with pill) and

control (no pill)

Blinded parallel

groups RCT

Supplement n = 9;

placebo, n = 7;

control group (no

pills), n = 4

6 wk Supplement group lost

more fat (3.1 kg; P <

0.05) than other

groups and increased

RMR (2–3%)

Citrus aurantium may

assist individuals in

losing body fat, due to

increased energy and

reduced energy intake

expenditure. No

adverse events were


Kalman et al. (36) Ephedrine and

synephrine alkaloids

(SAs) (5 mg twice

daily) based product

vs. placebo with

exercise and diet



double blind

30 overweight

subjects; BMI > 27

8 wk 3.4 kg weight loss in

experimental group vs.

2.05 kg in placebo

(P < 0.05)

No adverse events;

findings indicate

apparent short-term

safety and efficacy of

ephedrine and



Armstrong et al.


Exercise program with

assignment to drug

(Ma Huang, bitter

orange, and guarana)

or placebo. Bitter

orange standardized

for 5 mg synephrine


trial—unclear if

study is blinded

Five overweight

males/14 females

44 days Supplement increased

fat loss (2.5 kg; P =

0.033) more than

placebo (0.5 kg))

Low statistical power,

no marked side effects

Greenway et al.

(38): Pilot 1

Two capsules


pantothenic acid,

40 mg; green tea leaf

extract, 200 mg;

guarana extract,

550 mg; bitter orange,

150 mg; white willow

bark extract, 50 mg;

ginger root, 10 mg;

proprietary charge


(L-tyrosine, L-carnitine,

naringin), 375 mg



double blind

Eight subjects (1:1

ratio) between

supplement group and

placebo group

8 wk Supplement group

gained more weight

(1.04 °æ 0.27 kg; P <

0.04) than placebo

and increased RMR

(but not at 8 wk)

CAP was not

efficacious for weight


Greenway et al.

(38): Pilot 2

m-Synephrine 20 mg Prospective,


double blind

Twenty subjects (1:1

ratio) between

supplement group and

placebo group

8 wk Supplement group lost

weight (0.8 °æ 3.4 kg;

not significant) in 8

wk, and increased

RMR in 8 wk. No

control group was

used (Greenway,



November 1, 2009)

m-Synephrine was not

efficacious for weight


Abbreviations: BMI, body mass index; CAP, Citrus aurantium product; RCT, randomized, controlled trial; RMR, resting metabolic rate.

and fat percentage. No significant changes were noted in

resting energy expenditure, blood chemistries, or dietary

intake between the placebo and experimental groups.

In a double-blind, placebo-controlled, randomized

trial, Colker et al. found that subjects receiving a

combination of C. aurantium, caffeine, and St. John’s wort,

along with diet and exercise protocols, lost a statistically

significant amount of body weight. Analysis comparing

changes in this group with those in placebo or control

groups on the same diet and exercise regimen did not

show significant differences, though loss of fat mass was

significantly greater in the experimental group (35). BP,

heart rate, electrocardiographic, blood, and urine analyses

were not significantly different between the groups.

Another randomized trial (36) of 30 overweight

adults investigated the effects of supplementation, along

with a cross-training exercise regimen and dietary education

program compared with exercise and dietary

education alone on body composition. Supplementation

included ephedrine, SAs, caffeine, and calicine.

Greater weight and fat loss occurred for the supplement

group compared with the exercise–diet only


Overall, studies indicate a weight loss of 2.4–3.4 kg

among participants using SAs, while placebo groups lost

0.94–2.05 kg, suggesting the plausibility of some weight

loss benefit from SA supplementation, beyond diet and

exercise alone. However, these studies do not separate

Bitter Orange 55

the effects of C. aurantium or SAs from other ingredients,

particularly ephedrine and caffeine.

Metabolic Rate and Cardiovascular Effects

Several studies have evaluated the effects of acute administration

of SAs on cardiovascular indicators. Kalman et al.

(39) tested a product containing 335 mg Ma Huang standardized

for 20 mg ephedrine alkaloids, 910 mg guarana

standardized for 200 mg caffeine, and 85 mg bitter orange

standardized for 5 mg SAs per two capsules. Twentyseven

overweight adults were randomized to treatment

or placebo for 14 days. BP, heart rate, electrocardiogram,

and Doppler echocardiograms were evaluated before and

after treatment. Ingestion of this commercial weight loss

supplement did not produce any detectable cardiovascular

side effects.

Penzak et al. (10) examined cardiovascular outcomes

in 12 normotensive individuals who were administered

8 oz of Seville orange juice (containing 13–14 mg SAs)

and water in a crossover fashion, followed by a repeat

ingestion 8 hours later. No changes in cardiovascular indices

(BP, maximal arterial pressure, and heart rate) were


Thomas et al. (40) evaluated the cardiovascular effects

of 10 mg oral SAs in healthy volunteers over a 4-hour

period on impedance cardiography and forearm plethysmography.

Elevation in total peripheral resistance was observed

30–60 minutes after dosing, although other hemodynamic

indexes were not affected.

Hemodynamic effects were observed in a crossover

design, placebo-controlled study (41) with the administration

of Xenadrine, a CAP that contains a variety of other

potentially bioactive substances, including green tea extract,

cocoa extract, yerba mate, ginger root, grape seed

extract, and others. However, these increases in heart rate,

and systolic and diastolic BP were not observed with administration

of Advantra Z, which contains C. aurantium

alone, even at an eightfold higher dose.

Haller et al. (42) evaluated a dietary supplement

[Ripped Fuel Extreme Cut, containing synephrine from

C. aurantium (presumably p-synephrine) and caffeine] in

10 healthy adults (three women) aged 20–31 years. Each

subject was given one dose of the dietary supplement

under three conditions: (i) resting conditions (without

placebo); (ii) moderately intense exercise; and (iii) placebo

plus moderately intense exercise in a three-arm, randomized,

crossover study. Greater postexercise diastolic BP

was seen with the dietary supplement plus exercise than

with placebo plus exercise. There were no obvious supplement

effects on postexercise HR, systolic BP, or body


Bui et al. (43) reported the effect on BP (systolic

and diastolic) and heart rate over 6 hours after one

dose of a CAP (Nature’s Way Bitter Orange) on 15

young, healthy adults in this prospective, randomized,

double-blind, placebo-controlled, crossover study. Systolic

and diastolic BP increased significantly within the

1–5 hours time period in comparison with the placebo

group with the peak being 7.3 °æ 4.6 mm Hg, while the

4–5 hours time period increase was 2.6 °æ 3.8 mm Hg after

consumption in comparison with the placebo group

with the peak being 4.2 °æ 4.5 beats/minute, while

heart rate was significantly elevated 2–5 hours after


In one study of obese adults, increases in resting

metabolic rate (RMR) were observed with C. aurantium,

both alone and with food, beyond the thermic effect of

food (TEF) alone (44). (RMR is a measure of the energy

required to maintain basic physiological function while

the body is at rest.) However, another recent investigation

(45) found that the thermic response to CAPs increased in

women only, who had lower TEF than men at baseline.

After the intervention, TEF did not differ by gender. BP

and pulse rate were not affected, but epinephrine secretion

increased. In normal weight adults, an increase in RMR

was also found when the extract was taken with a meal

(46).Noadverse changes in pulse rate or BP were reported.

Finally, the effects of two dietary supplement formulas

onRMRand other metabolic indicators were evaluated

(47). When compared with placebo, Formula A (containing

ephedra, guarana, green tea, yohimbe, and quercetin)

and Formula B (containing C. aurantium, jing jie, fang feng,

guarana, green tea, yohimbe, and quercetin) resulted in increased

total RMR, decreased respiratory exchange ratio

toward fat burning, and increased body core temperature.

Heart rate and RMR increased at each 15-minute interval

with Formula A only. BP increased with both, but to a

greater extent with Formula A.



Nykamp et al. (48) describe a case of acute lateral-wall

myocardial infarction co-occurring with consumption of

CAPs in a 55-year-old woman with undetected coronary

vascular disease. She reported taking a multicomponent

dietary weight loss supplement containing 300 mg of bitter

orange over the preceding year.

Consumer Reports article (49) describes a 21-yearold

woman who took ephedra-free Xenadrine EFX (which

contains C. aurantium). After 3 weeks on the supplement,

she suffered a seizure. Her neurologist believes the bitter

orange in the supplement was the most likely the cause,

though the basis for this conclusion is unknown.

Nasir et al. (50) described exercise-induced syncope

in a healthy 22-year-old woman that occurred 1 hour after

a second dose of Xenadrine EFX, a weight loss supplement

that contains, among other compounds, ephedrine and

synephrine. The electrocardiography revealed prolongation

of the QT interval, which resolved in 24 hours.

Bouchard et al. (51) report a case of a 38-year-old

male patient with ischemic stroke that occurred after taking

a CAP for 1 week. The patient reportedly had no relevant

medical history or major atherosclerotic risk factors

and took no other medications.

Gray andWoolf (52) reported a case of CAPs use by

an adolescent with anorexia nervosa and raised concerns

that the SAs may have masked bradycardia and hypotension

while exacerbating her weight loss. Firenzuoli et al.

(53) report a case of a 52-year-old woman that had an

allergic reaction after taking a CAPs product.

Sultan et al. (54) reported a case of a 52-year-old

woman with ischemic colitis that occurred 1 week after

consumption of a CAP (Natural Max Skinny Fast,

containing bitter orange). She reported no known drug

56 Haaz et al.

Table 2 Summary of Effects, Safety, and Efficacy of Citrus aurantium

Physiological effects Effects on weight Effects on body composition Safety

Variable changes in BP in animals;

generally stable BP, heart rate, pulse

rate, blood and urine measures in

humans; inconsistent changes to

resting metabolic rate

Weight loss documented in rodents;

weakly supported in humans, as

studies used multiple supplements or

did not find significant difference

from controls

Limited support for loss of fat mass in

human studies, noting a trend or

using multiple supplements; for

animals, some increased lipase


Inconsistent mortality data in

rodents; some evidence of

elevated BP. Results not

consistent from study to study,

but this may be a function of

small sample sizes used in most

studies. Several case reports of

serious adverse events

allergies and took no other medications. Symptoms resolved

over 24–48 hours with conservative management

after the supplement was discontinued.

Health Canada reported that fromJanuary 1, 1998, to

February 28, 2004, it received 16 reports in which products

containing bitter orange or synephrine were suspected

of being associated with cardiovascular events, including

tachycardia, cardiac arrest, ventricular fibrillation, transient

collapse, and blackout. All cases were considered

serious (55).

Adverse events from CAPs are currently fairly rare

in scientific literature. As CAPs are used more widely in

place of ephedrine-containing products, any potentially

harmful effects may be clarified over time.


The Safety of CAPs

Some have hailed the potential therapeutic value of CAPs

(1), while others have warned about possible safety concerns

(33). The safety concerns pertain primarily to adverse

cardiovascular and cerebrovascular effects. Information

on the safety of CAPs comes from the three sources

described above: animal studies, clinical trials, and case

reports. To date, no large epidemiologic (case control or

cohort) studies have evaluated the safety of CAPs.

Of course, one cannot extrapolate the safety of CAPs

from short-term studies used for one indication (e.g., several

days for relief of nasal congestion among the general

population) to long-term studies use for another indication

(e.g., several months or years for weight loss

among obese individuals). Although substantial safetyrelated

data exist for CAPs (13,56), there is no published

human weight loss trial of CAPs with more than 20 participants

or for a duration of more than 7 weeks.

It is important to note that the majority of

studies evaluating the safety of CAPs are performed

with normotensive subjects. However, because hypertension

is a common comorbidity associated with overweight/

obesity, studies that evaluate the effects of CAPs

on BP should also be conducted with obese hypertensive


While C. aurantium extracts have been used in a variety

of cultures for thousands of years, they have not been

traditionally utilized for long periods of time, or specifically

for weight loss (1). As such, there is little, if any, basis

for making definitive statements about the intermediate

or long-term safety/risk of CAPs used for weight loss.

Table 2 summarizes the physiological effects, safety, and

weight loss efficacy of C. aurantium.



Given the dearth of weight loss trials, the optimal dose

(if one exists) of C. aurantium or its SA constituents for

weight loss is unknown. Table 3 highlights some relevant

dosage information. Although generalizing across species

and compounds is difficult and can only provide a limited

basis for conjecture, the following comparisons with

ephedrine can be made. We analyzed data (12) in which

ephedrine or SAs was given to mice. Regression of weight

and food intake on dose of ephedrine or SAs yielded

slopes (in absolute value) that were approximately four

to six times greater for ephedrine than for SAs. Based on

linear projections, it would take four to six times the dose

of SAs (in these mice) to achieve equivalent reduction in

intake and body weight as for ephedrine. In human studies

of ephedrine, doses of about 50 mg per day begin to be

effective (57). Although an extrapolation, this might suggest

a useful clinical dose for SAs as high as 240–360 mg

Table 3 Dosage Information on Citrus aurantium or Synephrine Alkaloids (SAs)


5–14 mg/day Citrus aurantium extract with SAs has been used (34–36) and no serious adverse events were reported. These doses purportedly

showed efficacy, but products tested included substances beyond C. aurantium, notably ephedrine which we know to be effective for

weight loss. We believe that these doses of SAs are very unlikely to be effective when used without ephedrine

32 mg/day The nasal decongestant Endal (60) contains 20 mg of m-s per tablet and two tablets per dose twice per day are recommended

120 mg/day Via C. aurantium extract, SAs are marketed in over-the-counter (OTC) products for weight loss. In products, such as Nutres Lipo 6

(61), the directions suggest that for “extreme fat loss” a recommended dosage is two capsules three times per day. The SA content

per capsule is 20 mg; this provided a maximal recommended dose of 120 mg/day

300 mg/day According to Clarke’s Analysis of Drugs and Poisons (62), oxedrine (p-synephrine) is used clinically at ∼300 mg/day

1000 mg/day Minimum adult lethal dose of m-s (63)

Bitter Orange 57

per day. From a safety point of view, SAs (per equal

weight) have lower potential to raise BP than ephedrine;

however, nearly all commercial preparations of SAs also

contain caffeine, which might compound any cardiovascular

effects. In the absence of caffeine, human studies

suggest that 15–30 times the dose of SAs are required to

elevate BP to the same degree as ephedrine (58,59). This

suggests that such high doses might be well tolerated,

but clearly more data are needed, particularly regarding

potential synergistic effects of CAPs components.

SAs appear to be readily absorbed after oral administration

(63). About 80% of oral doses are excreted in

the urine within 24 hours. After single oral doses, peak

plasma concentrations are typically reached in 1–2 hours.

Plasma half-life is ∼2–3 hours. Sympathomimetic drugs

for weight loss are typically given TID before meals (64)

reducing the evening dose if sleep problems arise.


Topical application (as with aromatherapy or antifungal

uses) of CAPs may result in photosensitivity for fair skinned

individuals (65) (possibly due to photosensitizing

furanocoumarins that occur in the rinds of certain

citrus species, especially immature fruits). Although

rare, this has also occurred after oral ingestion. To reduce

this risk, exposure to ultraviolet light can be minimized.

Caution is recommended for use in children, as it

may conceivably produce toxic effects (66). Some sources

advise that CAPs should be avoided by women who are

pregnant or breastfeeding (7,67), while others claim that

CAPs can be used safely during pregnancy (66). While

effects on BP are unclear, those with hypertension, tachyarrhythmia,

or narrow-angled glaucoma may consider

refraining from use of CAPs until further evidence confirms

their safety (67).CAPs could also possibly exacerbate

symptoms for those with stomach or intestinal ulcers (68).


Because CAPs may increase stomach acid, they could potentially

reduce the efficacy of acid-lowering drugs, such

as antacids and ulcer medications (69). Although a speculative

precaution, those taking medications containing

SAs, including some cold medications and monoamine oxidase

inhibitors (MAOIs), should consider the combined

dose of these products with the SAs present in CAPs formulations

and possible multiplicative effects (68,69). It has

been suggested that CAPs could interfere with the activity

of drugs that are metabolized by the liver enzyme cytochrome

P450-3A, CYP3A (70,71). A recent comment in

Experimental Biology and Medicine noted that some research

on drug effects have utilized parts of the plant or

methods of administration that may not be applicable to

oral consumption of currently marketed dietary supplements


The safety and efficacy of CAPs and SAs for weight

loss are not well established. While existing literature

demonstrates plausibility for reducing weight, previous

trials were not designed to rigorously evaluate safety and

efficacy. Doing so will require better-designed randomized

clinical trials with large sample sizes, reliable well established

outcome measures, and active surveillance of

side effects and adverse events. To better understand the

effects of CAPs or SAs specifically, studies will need to test

these components without combining them with other ingredients

postulated to have antiobesity effects. It would

also be worthwhile to examine differences between the

types of synephrine-containing compounds that are derived

from various sources and how this influences the

consistency and potency of supplements.


The writing of this entry was supported in part

by NIH grant nos. P30DK056336, AR49720–01A1, and

T32HL072757. The opinions expressed are solely the responsibility

of the authors and do not necessarily represent

the official views of the NIH or any other organization

with which the authors are affiliated.

Disclosure: Dr. Allison has received grants, honoraria,

consulting fees, and donations from numerous

companies, government agencies, and nonprofit organizations

with interests in obesity in general and dietary

supplements in particular, including organizations litigating

cases involving C. aurantium.


1. 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.

2. Pellati F, Benvenuti S, Melegari M, et al. Determination of

adrenergic agonists from extracts and herbal products of

Citrus aurantium L. var. amara by LC. J Pharm Biomed Anal

2002; 29:1113–1119.

3. Food and Drug Administration, HHS. Final rule declaring

dietary supplements containing ephedrine alkaloids adulterated

because they present an unreasonable risk: final rule.

Fed Regist 2004; 69(28):6787–6854.

4. BrownD. The Royal Horticultural SocietyNewEncyclopedia

of Herbs and their Uses. London, England: Dorling Kindersley,


5. Gonzalez-FerraraMM.Plantas Medicinales de Mexico. Monterey,

Mexico: Grupo Vitro, 1998.

6. Molina GV. Plantas Medicinales en el Pais Vasco. San Sebastian,

Spain: Editorial Txertoa, 1999.

7. Bensky D, Gamble A, Kaptchuk T. Chinese Herbal Medicine:

Materia Medica. Seattle,WA: Eastland Press, Inc., 1993.

8. Illes J. Beauty Secrets of Ancient Egypt. In: InnerCity Oz,

Inc., 2000.

mag4.htm. Accessed April 3, 2010.

9. Raintree Nutrition. Orange Bitters. Austin, TX: Raintree Nutrition,

Inc., 2004.

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. 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 (Maywood) 2004;


58 Haaz et al.

12. Allison DB, Cutter G, Poehlman ET, et al. Technical reports:

exactly which synephrine alkaloids does Citrus

aurantium (bitter orange) contain? Int J Obes 2005; 29(4):


13. Brown CM; National Toxicology Program. NTP toxicology

carcinogenesis studies of phenylephrine hydrochloride (CAS

no. 61-76-7) in F344/N rats and B6C3F1 mice (feed studies).

Natl Toxicol Program Tech Rep Ser 1987; 322:1–172.

14. Brown CM, McGrath JC, Midgley JM. Activities of

octopamine and synephrine stereoisomers on alphaadrenoceptors.

Br J Pharmacol 1988; 93:417–429.

15. Jordan R, Midgley JM, Thonoor CM, et al. Beta-adrenergic

activities of octopamine and synephrine stereoisomers on

guinea-pig atria and trachea. J Pharm Pharmacol 1987;


16. Kim KW, Kim HD, Jung JS. Characterization of

antidepressant-like effects of p-synephrine stereoisomers.

Naunyn Schmiedebergs Arch Pharmacol 2001; 364:21–26.

17. Starke K. A history of Naunyn-Schmiedeberg’s archives

of pharmacology. Naunyn Schmiedebergs Arch Pharmacol

1998; 358:1–109.

18. Bour S,VisentinV, Prevot D, et al. Moderate weight-lowering

effect of octopamine treatment in obese Zucker rats. J Physiol

Biochem 2003; 59:175–182.

19. Thomas DG, Robson SC, Redfern N, et al. Randomized trial

of bolus phenylephrine or ephedrine for maintenance of arterial

pressure during spinal anaesthesia for caesarean section.

Br J Anaesth 1996; 76:61–65.

20. Dittrich A, Albrecht K, Bar-Moshe O, et al. Treatment of

pharmacological priapism with phenylephrine. J Urol 1991;


21. Eyeson-Annan ML, Hirst LW, Battistutta D, et al. Comparative

pupil dilation using phenylephrine alone or in

combination with tropicamide. Ophthalmology 1998; 105:


22. Astrup A. Thermogenic drugs as a strategy for treatment of

obesity. Endocrine 2000; 13:207–212.

23. National Toxicology Program. NTP toxicology carcinogenesis

studies of ephedrine sulfate (CAS no. 134-72-5) in F344/N

rats and B6C3F1 mice (feed studies). Natl Toxicol Program

Tech Rep Ser 1986; 307:1–186.

24. Stricker EM, Verbalis JG. Caloric and noncaloric controls of

food intake. Brain Res Bull 1991; 27:299–303.

25. Carpene C, Galitzky J, Fontana E, et al. Selective activation

of beta3-adrenoceptors by octopamine: comparative studies

in mammalian fat cells. Naunyn Schmiedebergs Arch Pharmacol

1999; 359:310–321.

26. Yeh SY. Comparative anorectic effects of metaraminol and

phenylephrine in rats. Physiol Behav 1999; 68:227–234.

27. Mooney RA, McDonald JM. Effect of phenylephrine on lipolysis

in rat adipocytes: no evidence for an alpha-adrenergic

mechanism. Int J Biochem 1984; 16:55–59.

28. Desfaits AC, Lafond J, Savard R. The effects of a selective

alpha-1 adrenergic blockade on the activity of adipose tissue

lipoprotein lipase in female hamsters. Life Sci 1995; 57:705–


29. Spurlock ME, Hahn KJ, Miner JL. Regulation of adipsin and

body composition in the monosodium glutamate (MSG)-

treated mouse. Physiol Behav 1996; 60:1217–1221.

30. Heo M, Faith MS, Allison DB. Power and sample size for

survival analysis under the Weibull distribution when the

whole lifespan is of interest. Mech Ageing Dev 1998; 102:45–


31. Cantox Health Sciences International. Safety Assessment and

Determination of a Tolerable Upper Limit for Ephedra. Ontario,

Canada: Cantox Health Sciences International, 2000.

32. Arbo MD, Schmitt GC, LimbergerMF, et al. Subchronic toxicity

of Citrus aurantium L. (Rutaceae) extract and p-synephrine

in mice. Regul Toxicol Pharmacol 2009; 54:114–117.

33. Calapai G, Firenzuoli F, Saitta A. Antiobesity and cardiovascular

toxic effects of Citrus aurantium extracts in

the rat: a preliminary report. Fitoterapia 1999; 70:586–


34. Iaccarino G, Rockman HA, Shotwell KF, et al. Myocardial

overexpression of GRK3 in transgenic mice: evidence for

in vivo selectivity of GRKs. Am J Physiol 1998; 275:H1298–


35. Colker CM, Kalman DS, Torina GC, et al. Effects of Citrus

aurantium extract, caffeine, and St. John’s wort on body fat

loss, lipid levels, and mood states in overweight healthy

adults. Curr Ther Res 1999; 60:145–153.

36. Kalman DS, Colker CM, Shi Q, et al. Effects of a weightloss

aid in healthy overweight adults: double-blind, placebocontrolled

clinical trial. Curr Ther Res 2000; 61:199–205.

37. Armstrong WJ, Johnson P,DuhmeS. The effect of commercial

thermogenic weight loss supplement in body composition

and energy expenditure in obese adults. J Exerc Physiol 2001;


38. Greenway F, de Jonge-Levitan L, Martin C, et al. Dietary

herbal supplements with phenylephrine for weight loss.

J Med Food 2006; 9(4):572–578.

39. Kalman D, Incledon T, Gaunaurd I, et al. An acute clinical

trial evaluating the cardiovascular effects of an herbal

ephedra-caffeine weight loss product in healthy overweight

adults. Int J Obes Relat Metab Disord 2002; 26:1363–1366.

40. Thomas SH, Clark KL, Allen R. et al. (A comparison of the

cardiovascular effects of phenylpropanolamine and phenylephrine

containing proprietary cold remedies. Br J Clin Pharmacol

1991; 32:705–711.

41. Haller CA, Benowitz NL, Jacob P. Hemodynamic effects of

ephedra-free weight-loss supplements in humans.AmJ Med

2005; 118:998–1003.

42. Haller AA, Duan M, Jacob P III, et al. Human pharmacology

of a performance-enhancing dietary supplement under

resting and exercise conditions. Br J Clin Pharmacol 2008;


43. Bui LT, Nguyen DT, Ambrose PJ. Blood pressure and heart

rate effects following a single dose of bitter orange. Ann

Pharmacother 2006; 40:53–57.

44. Pathak B, Gougeon R. Thermic effect of Citrus aurantium in

obese subjects. Curr Ther Res 1999; 60:145–151.

45. Gougeon R, Harrigan K, Tremblay JF, et al. Increase

in the thermic effect of food in women by adrenergic

amines extracted from Citrus aurantium. Obes Res 2005; 13:


46. Hedrei P, Gougeon R. Thermogenic Effect of Beta Sympathicomimetic

Compounds Extracted from Citrus aurantium.

Canada: McGill Nutrition and Food Science Center, Royal

Victoria Hospital, 1997.

47. Shugarman AE, Askew EW, Stadler DD, et al. Effect of thermogenic

dietary supplements on resting metabolic rate in

healthy male and female volunteers. Med Sci Sports Exerc

2004; 31:S164.

48. Nykamp DL, Fackih MN, Compton AL. Possible association

of acute lateral-wall myocardial infarction and bitter orange

supplement. Ann Pharmacother 2004; 38:812–816.

49. Dangerous supplements: still at large. Consum Rep 2004;


50. Nasir JM, Durning SJ, Ferguson M, et al. Exercise-induced

syncope associated with QT prolongation and ephedra-free

Xenadrine. Mayo Clin Proc 2004; 79:1059–1062.

51. Bouchard NC, Howland MA, Greller HA, et al. Ischemic

stroke associated with use of an ephedra-free dietary supplement

containing synephrine. Mayo Clin Proc 2005; 80:541–


52. Gray S, Woolf AD. Citrus aurantium used for weight loss by

an adolescent with anorexia nervosa. J Adolesc Health 2005;


Bitter Orange 59

53. Firenzuoli F, Gori L, Galapai C. Adverse reaction to an adrenergic

herbal extract (Citrus aurantium). Phytomedicine 2005;


54. Sultan S, Spector J, Mitchell RM. Ischemic colitis associated

with use of a bitter orange-containing dietary weight-loss

supplement. Mayo Clin Proc 2006; 81(12):1630–1631.

55. Health Canada warns Canadians not to use “Thermonex.”

Warning 2004-30.

advisories-avis/2004/2004 30-eng.php. Accessed April 3,


56. Bradley JG. Nonprescription drugs and hypertension.

Which ones affect blood pressure? Postgrad Med 1991; 89:


57. Pasquali R, Baraldi G, Cesari MP. A controlled trial using

ephedrine in the treatment of obesity. Int J Obes 1985; 9:93–


58. Lee A, Ngan Kee WD, Gin T. A quantitative, systematic review

of randomized controlled trials of ephedrine versus

phenylephrine for the management of hypotension during

spinal anesthesia for cesarean delivery. Anesth Analg 2002;


59. Cooper DW, Carpenter M, Mowbray P, et al. Fetal and

maternal effects of phenylephrine and ephedrine during

spinal anesthesia for cesarean delivery. Anesthesiology 2002;


60. Mikart Inc. Endal Nasal Decongestant. Atlanta, GA: Mikart

Inc., 2002.

61. Nutres Lipo 6.

nutrex/lipo6.html 2005, Boise, ID Bodybuilding.

com. Accessed April 3, 2010.

62. Moffat AC, Osselton MD, Widdop B, et al. Clarke’s Analysis

of Drugs and Poisons. London, England: Pharmaceutical

Press, 2004.

63. Sweetman SC. Phenylephrine. In: Martindale: The Complete

Drug Reference. London, England: Pharmaceutical Press,


64. Bray GA, Greenway FL. Current and potential drugs for

treatment of obesity. Endocr Rev 1999; 20:805–875.

65. Herbal Medicine: Expanded Commission E Monographs.

Newton, MA: Integrative Medicine Communications, 1999.

66. American Herbal Products Association’s Botanical Safety

Handbook. Boca Raton, FL: CRC Press, 1998.

67. Jellin JM. Natural Medicines Comprehensive Database.

Stockton, CA: Therapeutic Research Faculty, 2006.

68. Brinker F. Herb Contraindications & Drug Interactions.

Sandy, OR: Eclectic Medical Publications, 2001.

69. Jellin JM. Natural Medicines Comprehensive Database.

Stockton, CA: Therapeutic Research Faculty, 2002.

70. Guo LQ, Taniguchi M, Chen QY, et al. Inhibitory potential

of herbal medicines on human cytochrome P450-mediated

oxidation: properties of umbelliferous or citrus crude drugs

and their relative prescriptions. Jpn J Pharmacol 2001; 85:


71. Gurley BJ, Gardner SF, Hubbard MA, et al. In vivo assessment

of botanical supplementation on human cytochrome

P450 phenotypes: Citrus aurantium, Echinacea purpurea, milk

thistle, and saw palmetto. Clin Pharmacol Ther 2004; 76:428–


72. Dentali SJ. Comment on Citrus aurantium Minireview. Exp

Biol Med (Maywood) 2005; 230:102.