Orange Bitter Essential Oil

Posted on October 17, 2017

‘Bitter’ has been the most neglected taste all around the world and the truth is that bitter things
are often better for your fitness regime. On a deeper note, most of the medicines are bitter and
they pave way for the sweet fruit of health and harmony.
Unlike the sweet oranges, bitter oranges are not much favored mainly for its tart, astringent and
acidic taste. Since the ancient times, bitter oranges and the essential oil cold pressed from the
rind of these fruits have carried away the world of medicine with its enormous medicinal
values.

Known as Narange in Sanskrit, bitter orange is used in Ayurveda in the treatment of gout,
gastrointestinal problems, lack of appetite, anxiety and digestive disorders.
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Scientifically known as Citrus aurantium, bitter orange is an evergreen tree indigenous to the
tropical parts of Asia and Africa. Almost all the parts of this tree are used in extracting essential
oils due its healing values.

Essential oil extracted from the leaves and twigs of this tree is known as Petitgrain oil, the oil
distilled from the flowers of this tree is the celebrated Neroli oil and the oil extracted from the
peel of the bitter orange fruit is called as Bitter orange essential oil.

Historical importance of Bitter Orange:

The Traditional Chinese Medicine used bitter oranges as a natural carminative and tonic for
treating dyspepsia. They also used dried bitter oranges in the treatment of diarrhea, ptosis of the
anus and uterus, blood in feces and abdominal distention.

The rind of bitter orange fruits were used in Homeopathy for relieving abdominal pain,
headache, constipation, digestive disorders, weight loss and high blood pressure. Due to the
presence of the active ingredient synephrine, bitter oranges are used in herbal medicinal system
as an appetite suppressant and as a stimulant.
The Brazilian folklore medicine used bitter orange and its oil in treating insomnia and
anxiety. The ancient Europeans used it as a prophylactic and as a sedative for curing
nervous problems, gastrointestinal disorders, insomnia, sore throat and gout.
This medicinal herb has been in use in various cultures across the globe in the treatment of
cancer, anaphylactic shock, cardiac exhaustion, heartburn, fungal infections and certain other
heart problems.

The native Latin Americans used it in the preparation of a tonic for treating insomnia, lessening
anxiety and also as a laxative. It is also used in the United States as an effective aid in
preventing colon, breast and skin cancer.
In addition, bitter orange essential oil is used in flavoring baked goods, alcoholic beverages,
gelatins, candies, puddings, meat products, frozen desserts and certain other condiments. It is
also used as a marinade for meat in the Haitian, Cuban, Nicaraguan and Dominican cooking.

Therapeutic properties and constituents of Bitter orange essential oil:

The remedial properties of this oil are antiseptic, carminative, sedative, stomachic, digestive,
antidepressant, anti-hyper cholesterolemic, tranquilizer, anti-inflammatory, choleretic,
antifungal and antibacterial. Synephrine, tyramine metabolites N-methyltyramine, pinene,
carotenoids, limonene, cymene, camphene, octopamine, ocimene and few other alkaloids are its
major chemical constituents.
Ayurvedic health benefits of Bitter orange essential oil:
Ayurveda is the oldest of all the healing methodologies in the world and it still flourishes due to
the simplicity it preaches and practices in its remedial rule. According to this ancient
science, every individual is a part of nature and his/her poor health and good health
depends upon their harmony with nature.
Sickness in Ayurveda is a strong symbol that the individual’s system is out of balance with
nature and needs immediate assistance with natural remedies like essential oils, herbal
medications, yoga, healthy lifestyle and meditation.

Ayurvedic remedies aim at treating the actual root cause of an illness instead of treating the
illness alone and suggests an Ayurvedic routine for preventing such illnesses in the future as
well.
Every human being according to Ayurvedic principle is unique with an individual constitution
that comprises of three energy elements known as doshas, namely vata, pitta and kapha. The
predominance of any one of these doshas determines the personality and characteristics of an
individual and imbalance of any of these doshas leads to diseases.
Ayurvedic treatments vary from individual to individual based upon their dosha predominance
and unique constitution. Bitter orange essential oil is said to increase vata and pitta doshas and
pacify kapha dosha.

The Ayurvedic health benefits of Bitter orange oil are:

1. Treats skin problems:
Bitter orange essential oil has been proved effective in treating numerous skin problems with its
antiseptic, antibacterial and antifungal properties. The rind of this fruit from which its essential
oil is extracted contains non-bitter flavonoids, which is known to have considerable venotonic
properties.

It is for this reason; bitter orange essential oil is used in cosmetics for preventing capillary
fragility. Bitter orange extracts are also used in the treatment of cellulite as it has the potent to
normalize the affected parts and stimulate the cutaneous tone of the skin.
The effects and unique properties of bitter orange essential oil in the Aromatherapy Workbook
by Shirley Price states bitter orange essential oil “help restore an acne skin to normal and is
prophylactic against the signs of ageing”. When applied to the affected area after blending 2
drops of bitter orange oil with coconut oil, the antifungal properties of this oil help in treating
fungal infections like athlete’s foot and ringworm.
Bitter orange oil also acts as a natural antiseptic and aids in clearing acne, cold sores, wounds,
psoriasis, eczema and certain other skin problems due to excessive stagnation of oil. You can
add 2 drops of bitter orange oil with refreshing carrier oil like jojoba oil or to your skin care
creams and lotions and gently massage onto the affected parts for quicker effects.

2. Enhances the digestive mechanism:

For more than thousands of years, bitter orange has been used in the world of Complementary
medicine for treating digestive problems like flatulence, dyspepsia, constipation, sluggish
digestion, loss of appetite, intestinal gas, nausea and indigestion.
Gently massaging your stomach with 2 drops of bitter orange oil blended with sesame oil can
help you enhance the entire process of digestion. You can also add 2 drops of this oil to your
bath tub to help with digestive disorders.

3. Assists in weight-loss:
Weight loss supplements with bitter orange formula are the most popular and the recent use of
bitter oranges in the therapeutic world. Numerous researches have proved the effectiveness of
bitter orange supplements in treating obesity.

“At present, Citrus aurantium may be the best thermogenic substitute for Ephedra” reveals the
Georgetown University Medical Center study on ‘Citrus aurantium as a thermogenic, weight-
reduction replacement for Ephedra’.
A recent research on ‘The safety of Citrus aurantium (bitter orange) and its primary
protoalkaloid p-synephrine’ states “The data indicate that based on current knowledge, the use
of bitter orange extract and p-synephrine appears to be exceedingly safe with no serious
adverse effects being directly attributable to these ingredients”.
It also notes that bitter orange extract and its principal protoalkaloidal constituent p-synephrine
are extensively used in weight management, weight loss and products promoting sports
performance.

A 2006 study on ‘Citrus aurantium and synephrine alkaloids in the treatment of overweight and
obesity’ by Johns Hopkins University School of Medicine, MD, USA states that there are
certain promising evidences that Citrus aurantium containing several compounds including
synephrine alkaloids is a safe alternative to Ephedra, which is a weight-loss supplement banned
in US for its adverse health effects.
To boost your metabolism and lessen energy absorption, you can massage your body with 2 to
3 drops of bitter orange oil blended with coconut oil or add 3 drops of this oil to your bath tub.

4. Alleviates stress and reduces anxiety:

Bitter orange oil has a much similar aroma to that of fresh tangy oranges. Inhaling the
energizing and enlivening fragrance of this oil especially during the early hours of the day
promises a serene atmosphere and instills complete calmness in your mind.
This is why Ayurvedic healing suggests the use of bitter orange oil during your meditation
practice. Add 1 drop of bitter orange oil to your diffuser or air freshener and start your deep
meditation after which you will feel a never before freshness and increase in your confidence
level.

The Aromatherapy expert, Dr. Vivian Lunny recommends an invigorating bath blend with 2
drops of bitter orange oil, 1 drop of neroli oil and 2 drops of petitgrain oil for reducing
anxiety, lethargy and tiredness.
When added to your warm bathing water especially after a tiring and stressful day, this blend is
said to give a new lease of life, augment stress relief, promote relaxation and stimulate
positive feelings. You can also add 1 drop of bitter orange oil to your handkerchief or to your
pulse points to renew yourself throughout the day.
Other benefits:
Bitter orange essential oil is also used in treating chronic fatigue syndrome, intestinal ulcers,
lowering blood sugar level in diabetic patients, sleep disorders, joint pain, muscular aches,
bruises, cold and certain other liver and gall bladder problems.

It is also used in making soaps, cleaning products, disinfectants, cosmetics, perfumes,

pharmaceuticals, eau de colognes and certain other household cleaners. Bitter orange oil is also
used as a commercial flavoring agent in foods and beverages in many countries.

Disclaimer:
Pure and organic essential oils are highly concentrated liquids so always use it after diluting in
suitable carrier oils. Never use essential oils internally. Citrus oils in general have a photo-toxic
effect so avoid going out in the sun immediately after using it on your skin.

Pregnant women, nursing mothers, children and people suffering from hypertension and
glaucoma should avoid using bitter orange oil. Always consult your Ayurvedic practitioner
before choosing the right essential oils for your unique individual constitution.

Bitter Orange Essential Oil – Possible Skin Issues:

Greener Life Diamond – Bio-Healthy Score => 3 Possible Skin Issues:

See => http://www.essentialdepot.com/GreenerLifeDiamond.html
Bitter orange oil exhibits mild photosensitivity effects if the oil is oxidized, which might cause
irritation and hyper-pigmentation of the skin and this happens when visible sunlight gets in
touch with the skin for up to 12 hours of usage. The major cause being the response of the
chemical components that are photoactive in nature attracts light and ends up in toxicity via
molecular alterations.

The safe dermal use level of Bitter orange oil by the International Fragrance Association
(IFRA) is 1.25%, specifically to thwart phototoxicity in the products used for topical
application and not for soaps, shampoos and other bath preparations. This No-observed-
adverse-effect-level (NOAEL) is based on various studies with Bitter orange oil on mice and
swine, where the No-observed-effects-level (NOEL) was proved as 6.25%.

Besides, Bitter orange oil is Generally Recognized As Safe (GRAS) by the FDA(Food and
Drug Administration). “There are no contraindications but that photosensitization may occur in
fair-skinned individuals”, quotes The German Commission E monograph for Bitter orange peel.
The major chemical constituent responsible for the skin sensitization and mild irritation of
Bitter orange oil is Limonene, which accounts to about 90% of this oil and certain other
furanocoumarins.

According to European regulations, essential oils with furanocoumarins should be used in such
a way that the overall level of bergapten does not surpass 15 ppm (parts per million) in ready-
to-use cosmetic products meant for use on the skin surface that are exposed to sunlight (other
than wash-away products) and 1 ppm in sunscreen and bronzing items.

Use Bitter orange oil only for external use and ingestion of this oil should be avoided strictly,
as internal use of this oil has adverse effects according to various reports. Medical research
studies state that the presence of stimulants like octopamine, amines synephrine (an alkaloid
with almost the related chemical structure to ephedrine in Ephedra – Ma-Huang) and N-
methyltyramine are responsible for the cardiovascular toxicity of Bitter orange and this is also
reported to cause increase in blood pressure and vasoconstriction.
It is recommended to avoid the use of Bitter orange in patients with tachyarrhythmia,
hypertension and narrow-angle glaucoma, mainly due its potent to cause additive effects.
Overdose of synephrine in children overdose ended up in tachycardia, nausea, quick increase in
blood pressure and irritation. Certain researches witness the effect of Bitter orange in
restraining human cytochrome P450 3A (CYP3A) in the test tube studies.
Just like Grapefruit, Bitter orange is said to hold back a vital enzyme in the small intestine, and
this may possibly have an effect on the levels of blood, when taking certain medications like
antiviral, anti-anxiety, antidepressant drugs, statins and calcium channel blockers and along
with the intake of caffeine.
Care should be taken if Bitter orange oil is used in massage in the abdominal area, as essential
oils penetrate quickly through the skin, reach the bloodstream and may cause adverse effects. It
is not recommended to take Bitter orange products when using other prescribed medications,
except under strict medical supervision.

Furocoumarins are also used in various remedies on par with the long-wave ultraviolet light
therapy for the healing of mycosis fungoides, vitiligo and psoriasis.

Reference Links Substantiating Possible Skin Issues of Bitter Orange Oil:

1. Bitter Orange by University of Michigan Health System
2. Bitter Orange, Sour News by University of California, Berkeley Wellness
3. Bitter Orange Peel and Synephrine by American Botanical Council
4. Bitter Orange, American Herbal Products Association’s Botanical Safety Handbook,
Second Edition by Zoe Gardner, Michael McGuffin
5. Bitter Orange by Drugs.com
6. Essential Oil Safety: A Guide for Health Care Professionals By Robert Tisserand,
Rodney Young
Thought for the day:
The trees that are slow to grow bear the best fruit. -Moliere
Suggested Reading:
1. Citrus Essential Oils: Flavor and Fragrance  from Wiley
 2. Citrus Oils: Composition, Advanced Analytical Techniques, Contaminants, and
Biological Activity (Medicinal and Aromatic Plants – Industrial Profiles)from CRC
Press
3. Aromatherapy Workbook: A Complete Guide to Understanding and Using Essential
Oils by Shirley Price
4. Ayurveda & Aromatherapy: The Earth Essential Guide to Ancient Wisdom and Modern
Healing by Dr. Light Miller, Dr. Bryan Miller
Reference Link:
1. Bitter orange by Wikipedia
2. Citrus aurantium and synephrine alkaloids in the treatment of overweight and obesity by
Johns Hopkins University School of Medicine, MD, USA published in PubMed
3. Bitter Orange by Drugs.com
4. The safety of Citrus aurantium (bitter orange) and its primary protoalkaloid p-synephrine
by Creighton University Medical Center, NE, USA published in PubMed

5. BITTER ORANGE
Also Known As:
Aurantii Fructus, Aurantii Fructus Immaturus, Aurantii
Pericarpium, Aurantium, Bigarade, Bigarade Orange, Bitter Orange Flower, Bitter Orange
Peel, Chao Zhi Ke, Chisil, Citrus Aurantium Fruit, Extrait de Zeste d'Orange, Fleur d'Orange
Amère, Flos Citri Auranti, Fructus Aurantii, Fructus Aurantii Immaturus, Green
Orange, Kijitsu, Marmalade Orange, Methyl-Synephrine, Methyl-Synephrine HCl, Méthyl-
Synéphrine HCl, Methyl Synephrine, N-Methyltyramine, Naranja Amarga, Neroli
 
Oil, Norsynephrine, Octopamine, Octopamine HCl, Orange Amère, Orange de Séville, Orange
Peel Extract, Orange Verte, Seville Orange, Shangzhou Zhiqiao, Sour
Orange, Synephrine, Synéphrine, Synephrine HCl, Synéphrine HCl, Synephrine
Hydrochloride, Zeste d'Orange Amère, Zhi Ke, Zhi Qiao, Zhi Shi.
CAUTION: See separate listings for Bergamot Oil, Oswego Tea, Raspberry Ketone, and Sweet
Orange.
Scientific Name:
Citrus aurantium, synonyms Citrus amara, Citrus bigarradia, Citrus vulgaris.
 
Family: Rutaceae.
People Use This For:
  Orally, bitter orange peel is used as an appetite stimulant and suppressant and for
dyspepsia. Bitter orange fruit and peel are also used orally for weight loss, increasing lean
body mass, body building, improving athletic performance, nasal congestion, allergic rhinitis,
and chronic fatigue syndrome (CFS). The bitter orange flower and its oil are used orally for
gastrointestinal (GI) disturbances, duodenal ulcers, constipation, regulating blood lipid
levels, lowering blood sugar in diabetes, hyperlipidemia, blood purification, functional
disorders of liver and gallbladder, stimulation of the heart and circulation, frostbite, as a
sedative for sleep disorders, for preoperative anxiety and sedation, for kidney and bladder
diseases, general feebleness, anemia, imbalances of mineral metabolism, impurities of the
skin, hair loss, for flatulence, and for cancer. Other uses include prolapsed uterus, prolapsed
anus or rectum, diarrhea, and blood in the stools. 
Topically, bitter orange peel and oil are used for tinea corporis, tinea cruris, and tinea pedis
 along with inflammation of the eyelid, conjunctiva, and retina. Bitter orange is also used for
retinal hemorrhage, exhaustion accompanying colds, headaches, neuralgia, muscular pain,
rheumatoid arthritis, bruises, phlebitis, and bed sores. 
In aromatherapy, the essential oil of bitter orange is used topically and by inhalation as an
analgesic. 
In foods, bitter orange oil is used as a flavoring agent. 
In manufacturing, bitter orange oil is used in pharmaceuticals, cosmetics, and soaps.
Safety:
LIKELY SAFE ...when used orally in amounts commonly found in foods. Bitter orange has
Generally Recognized as Safe (GRAS) status in the US (4912, 35751). 
POSSIBLY SAFE ...when bitter orange essential oil is used topically or by inhalation as
aromatherapy (6972, 7107). 
POSSIBLY UNSAFE ...when used orally for medicinal purposes. Bitter orange juice and
extract have been safely used, short-term in healthy adults in small controlled trials (2040,
11269, 15381, 35757, 35759, 91681). However, there is concern that bitter orange can cause
potentially severe adverse effects in some patients due to its stimulant effects. Although
findings have been mixed, there are several case reports of ischemic stroke, and
cardiotoxicity including tachyarrhythmia, cardiac arrest, syncope, angina, myocardial
 
infarction, ventricular arrhythmia, and death in otherwise healthy patients who have taken
bitter orange extract alone or in combination with other stimulants such as caffeine (2040,
6979, 12030, 13039, 13067, 14326, 14342, 91680). 
PREGNANCY AND LACTATION: LIKELY SAFE ...when used orally in the amounts found in
foods. Bitter orange has Generally Recognized as Safe (GRAS) status in the US (4912).
POSSIBLY UNSAFE ...when used orally for medicinal purposes. There are case reports of
cardiotoxicity including tachyarrhythmia, syncope, and myocardial infarction in otherwise
healthy adults who have taken bitter orange extract in combination with other stimulants
such as caffeine (2040, 6979, 12030, 13039, 91680). The effects of bitter orange on a fetus or in a
breast-feeding infant are not known; avoid using.
Effectiveness:
  POSSIBLY EFFECTIVE
Tinea corporis, tinea cruris, and tinea pedis. Applying bitter orange oil seems to help treat
tinea corporis (ringworm), cruris (jock itch), or pedis (athlete's foot) (6972). 
INSUFFICIENT RELIABLE EVIDENCE to RATE
Diabetes. Preliminary clinical research shows that drinking a tea made from the leaves of
Indian snakeroot and the fruit of bitter orange for 4 months decreases fasting and post-
prandial glucose levels, as well as hemoglobin A1c levels, in patients with type 2 diabetes
compared to placebo (35751). 
Dyspepsia. Preliminary clinical research shows that taking a specific product containing
bitter orange in combination with other ingredients (Zhizhu) three times daily for 4 weeks
has a markedly cured effective rate of 67% for functional dyspepsia compared with 45% of
patients taking a similar product containing sweet orange instead of bitter orange (35757).
Obesity. There is contradictory evidence about the effects of bitter orange on weight. One
preliminary clinical trial shows that a combination of bitter orange 975 mg, caffeine 528 mg,
and St. John's wort 900mg daily might help for weight reduction when used with caloric
restriction and exercise (11268). Additional preliminary study shows that taking a specific
combination product (Prograde Metabolism, Prograde Nutrition, Lutz, FL) containing bitter
 orange, raspberry ketone, caffeine, capsaicin, garlic, ginger, black pepper, cayenne pepper,
and chromium along with diet and exercise for 8 weeks significantly reduces body weight,
fat mass, hip and waist girth and increases lean body mass and energy levels compared to
placebo in overweight patients (91291). However, other preliminary clinical research suggests
that a different specific combination product (Charge, Labrada) containing bitter orange 150
mg, providing 9 mg synephrine, plus caffeine and several other ingredients taken twice daily
does not significantly reduce weight (15381). The effects of bitter orange alone on obesity are
unclear.
Preoperative anxiety and sedation. Clinical research suggests taking bitter orange blossom
distillate 1 mL/kg by mouth two hours prior to surgery reduces preoperative anxiety
compared to baseline (35759).
More evidence is needed to rate bitter orange for these uses.
Mechanism of Action:
  The applicable parts of bitter orange are the peel, flower, leaf, and fruit. Bitter orange has
numerous active constituents and pharmacological effects; however, the amount of each
constituent can vary depending on the plant part and preparation method used.
The flavonoid content is higher in the flowers than the leaves (6971). The flavonoids are also
present in the peel. These flavonoids include limonene, hesperidin, neohesperidin, naringin,
and tangaretin (12193).
The fruit and peel of bitter orange contain the adrenergic agonists synephrine and
octopamine (2080, 4800, 11267). Synephrine is structurally similar to epinephrine. Octopamine is
similar to norepinephrine (11995, 12193, 12378).
There are at least 6 isomers of synephrine. Different isomers of synephrine can have
somewhat different pharmacological effects. It is unclear which isomer or isomers are
contained in bitter orange. Some references suggest that bitter orange contains only p-
synephrine. Other references suggest that it contains only m-synephrine, which is also
known as phenylephrine. Phenylephrine (m-synephrine) is the alpha-adrenergic agent used
as an over-the-counter nasal decongestant (Neosynephrine). Some bitter orange product
labels indicate that the product contains both p-synephrine and m-synephrine. In laboratory
analysis, both of these isomers have been detected in at least one commercial bitter orange
product (13136). But it is unknown if this commercial bitter orange product may be spiked
with one or more synthetic synephrine isomers. More research is needed to determine
which isomer(s) of synephrine occur naturally in bitter orange extracts in order to better
understand the pharmacological effects of bitter orange products.
Synephrine and octopamine naturally occur in the human body. Trace amounts are part of
the pool of circulating amines in humans (12379).
In the body tyramine is converted to octopamine, which then gets converted to
synephrine (12193). Like tyramine, octopamine and synephrine are substrates of monoamine
oxidase (11995, 12378).
The exact physiological function of octopamine and synephrine is unclear. They were once
referred to as "false neurotransmitters," but it is now thought that they might act as true
neurotransmitters (12193).
Octopamine and synephrine might have a role in fat cell lipolysis. Octopamine seems to
have an insulin-like effect on glucose uptake by fat cells (11995). Preliminary research suggests
that migraine and cluster headaches might be related to excess levels of synephrine and
octopamine (11996).
Bitter orange peel seems to have beta-1 adrenergic activity (13657). Both synephrine and
octopamine are selective beta-3 adrenoreceptor agonists. Synephrine also appears to be an
alpha-1 agonist. Octopamine appears to also affect alpha-2 receptors (12193).
Fresh bitter orange fruit contains approximately 0.02% synephrine (11267). The concentration
tends to be smaller in larger fruits, and higher in smaller fruits. In freshly squeezed bitter
orange juice, the synephrine concentration is 57 mcg/mL (12193). Drying the fruit seems to
increase synephrine concentrations to approximately 0.35%. Dried extracts contain
approximately 3% synephrine. Octopamine levels are much lower, usually less than 0.03
percent (11267). Since octopamine concentration is so low, it's not known if its effects in
humans is significant.
Commercially available bitter orange extracts usually contain 1% to 6% synephrine. But
some manufacturers boost synephrine content to as much as 30%. These preparations are
often promoted for weight loss due to purported thermogenic effects (4800). In animal
models, synephrine causes weight loss, but also increases cardiovascular toxicity (6969).
Studies evaluating the effect of bitter orange on cardiovascular parameters have been
mixed. Some clinical research suggests that bitter orange, in combination with caffeine, can
increase systolic and diastolic blood pressure and heart rate in otherwise healthy
normotensive adults (13657). Taking a single dose of bitter orange 900 mg, standardized to 6%
synephrine (54 mg), seems to increase diastolic and systolic blood pressure and heart rate
for up to 5 hours in young, healthy adults (13774). But using half that dose of bitter orange
and providing half as much synephrine, does not seem to significantly effect blood pressure
or QT interval in healthy adults (14311). A manufacturer-sponsored study found no significant
changes in blood pressure, heart rate, or electrocardiogram measurements in normotensive
patients after 6 weeks of use; however, frequent hemodynamic monitoring was not
performed (11268).
Synephrine given intravenously in men increases systolic blood pressure, but does not seem
to increase diastolic blood pressure or heart rate (12193). Animal models suggest that bitter
orange can cause vasoconstriction and increase mean arterial pressure (MAP), but reduce
portal pressure (6975). 
Bitter orange plus a synthetic preparation of the active components synephrine and N-
methyltyramine have been used successfully to treat infectious shock in preliminary
research. N-methyltyramine seems to increase blood pressure by increasing norepinephrine
release (6978).
Preliminary research suggests that synephrine might have antidepressant effects, possibly
by promoting norepinephrine release (12376, 12377).
Bitter orange peel is also commonly used for dyspepsia due to its spasmolytic effects. Bitter
orange peel might also have anti-inflammatory activity, which might be due to the
flavonoids naringin and nobiletin (1281).
Bitter orange preparations have a variety of antimicrobial properties. The oil of the bitter
orange peel seems to have insecticidal activity (6973). Two flavonoids of the bitter orange
fruit, neohesperidin and hesperidin, also seem to have antiviral activity against rotavirus
infection (6976). Preliminary research indicates that bitter orange constituents auraptene,
marmin, tangeretin, nobiretin, and a psoralen compound, might have antitumor
effects (6974).
Although bitter orange is often included in muscle development products, preliminary
research suggests bitter orange does not affect muscle precursor cells called satellite cells,
which are thought to cause muscular hypertrophy (13773).
Bitter orange also contains furocoumarins. The furocoumarins bergapten and
 oxypeucedanin in bitter orange oil are photosensitizing (11019). The furocoumarins
bergamottin, dihydroxybergamottin, and bergapten in the fruit and juice can inhibit the
cytochrome P450 3A4 (CYP3A4) isoenzyme (7029). Bitter orange appears to selectively inhibit
intestinal CYP3A4, but not hepatic CYP3A4 (7029, 11269). These are the same constituents
found in grapefruit that are responsible for numerous drug interactions. However,
grapefruit juice contains a significantly higher concentration of these constituents than
bitter orange juice (7029). Research on the effects of bitter orange on P-glycoprotein is
conflicting (7029, 11269, 11270, 11362). Dihydroxybergamottin appears to inhibit CYP3A4, but not
P-glycoprotein (11270).
Adverse Reactions:
  Orally, bitter orange, which contains the adrenergic agents synephrine and octopamine,
might theoretically cause hypertension and cardiovascular toxicity (2040, 6969, 6979).
Synephrine is similar to phenylephrine and the ephedrine contained in the herb ephedra.
Theoretically, synephrine might cause similar side effects such as myocardial infarction (MI),
stroke, seizure, and other serious side effects.
Studies evaluating the effect of bitter orange on cardiovascular parameters have been
mixed. Some clinical research suggests that bitter orange in combination with caffeine can
increase systolic and diastolic blood pressure and heart rate in otherwise healthy
normotensive adults (13657). Taking a single dose of bitter orange 900 mg, standardized to 6%
synephrine (54 mg), seems to increase diastolic and systolic blood pressure and heart rate
for up to 5 hours in young, healthy adults (13774). But using half that dose of bitter orange
and providing half as much synephrine, does not seem to significantly effect blood pressure
or QT interval in healthy adults (14311). A manufacturer-sponsored study found no significant
changes in blood pressure, heart rate, or electrocardiogram measurements in normotensive
patients after 6 weeks of use; however, frequent hemodynamic monitoring was not
performed (11268). 
Case reports suggest that bitter orange might have significant adverse cardiovascular effects
in some patients. From 1998 to 2004, Health Canada has received 16 reports of serious
adverse cardiovascular reactions such as tachycardia, cardiac arrest, ventricular fibrillation,
blackout, and collapse. In two of these cases, the patient died. In almost all of these cases,
bitter orange was combined with another stimulant such as caffeine or ephedrine, or
both (14342). 
There are also several published cases of adverse cardiovascular reactions. Myocardial
infarction occurred in a patient without a history of cardiovascular disease who took
supplements containing bitter orange 300 mg for a year. The supplement also contained
guarana and green tea, both of which are sources of caffeine (12030).
In another case, a woman experienced unremitting tachycardia after taking a bitter orange
extract 500 mg containing 6% synephrine (30 mg). The patient discontinued bitter orange
extract for one month and then took it again. Upon this re-challenge, the patient
experienced another episode of unremitting tachycardia. Tachycardia resolved when the
bitter orange was discontinued (13067).
There is also a case report of syncope, tachyarrhythmia, and QT prolongation in a young,
healthy woman who took a specific combination product containing bitter orange
(Xenadrine EFX) just prior to exercising. This product also contained other stimulants
including caffeine, theobromine, phenylethylamine, tyramine, and others. The
tachyarrhythmia and QT interval normalized within 24 hours of discontinuing the
product (13039).
 In one case, a 57-year-old man developed symptoms of variant angina after taking a specific
combination product containing bitter orange (CortiSlim, Window Rock Health Laboratories)
for 35 days. Recurrent symptoms continued for several days after stopping the supplement
and the patient required extended treatment with vasodilators (14326). 
In another case, an otherwise healthy man experienced ischemic stroke after taking a
specific combination product containing bitter orange (Stacker 2 Ephedra Free) for 1 week.
The patient initially took 1 capsule daily and then increased to 2 capsules daily 4 days before
presentation and diagnosis. According to the product label at the time of this case, each
capsule provided approximately 6 mg synephrine and 200 mg caffeine (13091).
In another case, an otherwise healthy, African-American male with sickle cell trait,
developed severe rhabdomyolysis following ingestion of a specific weight loss product (Lipo
6, Nutrex Research Inc.), which contained synephrine and caffeine (16054).
Bitter orange has also been linked to a report of ischemic colitis. In one case, a 52-year-old
woman developed ischemic colitis after taking a bitter orange-containing supplement
(NaturalMax Skinny Fast, Nutraceutical Corporation) for a week. Symptoms resolved within
48 hours after discontinuing the supplement (15186).
Photosensitivity can also occur, especially in fair-skinned people (11019).
Interactions with Herbs & Supplements:
HERBS AND SUPPLEMENTS WITH HYPOGLYCEMIC POTENTIAL: Some clinical evidence
suggests that drinking a tea containing a combination of bitter orange and Indian snakeroot
reduces fasting and postprandial glucose levels in patients with type 2 diabetes who are
using antidiabetes drugs (35751). Theoretically, using bitter orange in combination with herbs
and supplements with hypoglycemic potential might have additive effects on blood glucose
levels and increase the risk of hypoglycemia. Some of these products include bitter melon,
cowhage, ginger, goat's rue, fenugreek, kudzu, willow bark, and others.
  HERBS AND SUPPLEMENTS WITH STIMULANT PROPERTIES: Herbs and supplements with
stimulant properties, such as ephedra, caffeine, and caffeine-containing supplements such
as coffee, cola nut, guarana, and mate, seem to increase the risk of hypertension and
adverse cardiovascular effects when used with bitter orange (6979, 13657).
PANAX GINSENG: Theoretically, Panax ginseng might prolong the QT interval on
electrocardiogram (ECG). Other stimulant products such as bitter orange also increase the
QT interval. Theoretically, combining Panax ginseng and bitter orange might have an
additive effect on the QT interval and increase the risk for arrhythmias (4322, 11355).
Interactions with Drugs:
ANTIDIABETES DRUGS
Interaction Rating = Moderate Be cautious with this combination.
Severity = Moderate • Occurrence = Possible • Level of Evidence = B
Some clinical evidence suggests that drinking a tea containing a combination of bitter
orange and Indian snakeroot reduces fasting and postprandial glucose levels in patients with
type 2 diabetes who are using antidiabetes drugs (35751). Theoretically, using bitter orange in
  combination with antidiabetes drugs might have additive effects on blood glucose levels and
increase the risk of hypoglycemia. Some antidiabetes drugs include glimepiride (Amaryl),
glyburide (DiaBeta, Glynase PresTab, Micronase), insulin, metformin (Glucophage),
pioglitazone (Actos), rosiglitazone (Avandia), and others.
CAFFEINE
Interaction Rating = Moderate Be cautious with this combination.
Severity = High • Occurrence = Possible • Level of Evidence = B
Bitter orange in combination with caffeine can increase blood pressure and heart rate in
otherwise healthy normotensive adults, and potentially increase the risk of serious
cardiovascular adverse effects (13657).
CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES
Interaction Rating = Minor Be watchful with this combination.
Severity = Mild • Occurrence = Possible • Level of Evidence = D
Octopamine, a constituent of bitter orange, weakly inhibits cytochrome P450 2D6 (CYP2D6)
enzymes in vitro (91878). Theoretically, bitter orange can increase the levels of CYP2D6
substrates. Some of drugs that are CYP2D6 substrates include amitriptyline (Elavil),
clozapine (Clozaril), codeine, desipramine (Norpramin), donepezil (Aricept), fentanyl
(Duragesic), flecainide (Tambocor), fluoxetine (Prozac), meperidine (Demerol), methadone
(Dolophine), metoprolol (Lopressor, Toprol XL), olanzapine (Zyprexa), ondansetron (Zofran),
tramadol (Ultram), trazodone (Desyrel), and others.
CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES
Interaction Rating = Moderate Be cautious with this combination.
Severity = Moderate • Occurrence = Possible • Level of Evidence = B
Bitter orange juice can inhibit cytochrome P450 3A4 (CYP3A4) metabolism of drugs (7029),
causing increased drug levels and potentially increasing the risk of adverse effects. However,
the extent of the effect of bitter orange on drug interactions is unknown. Bitter orange
selectively inhibits intestinal CYP3A4, but not hepatic CYP3A4. Its effect on P-glycoprotein,
which strongly overlaps with CYP3A4 interactions, is unclear (7029, 11269, 11270, 11362). It has no
effect on cyclosporine which seems to be more dependent on hepatic CYP3A4 and P-
glycoprotein than intestinal CYP3A4 (11270). Some possible drug interactions with bitter
orange include calcium channel blockers (diltiazem, nicardipine, verapamil),
chemotherapeutic agents (etoposide, paclitaxel, vinblastine, vincristine, vindesine),
antifungals (ketoconazole, itraconazole), glucocorticoids, cisapride (Propulsid), losartan
(Cozaar), fexofenadine (Allegra), and numerous others.
DEXTROMETHORPHAN (Robitussin DM, others)
Interaction Rating = Moderate Be cautious with this combination.
Severity = Moderate • Occurrence = Possible • Level of Evidence = B
Bitter orange juice can inhibit cytochrome P450 3A4 (CYP3A4) metabolism (11362), causing
increased dextromethorphan levels and potentially increasing the risk of adverse effects.
FELODIPINE (Plendil)
Interaction Rating = Moderate Be cautious with this combination.
Severity = Moderate • Occurrence = Probable • Level of Evidence = B
Consumption of bitter orange juice 240 mL can significantly increase felodipine levels. Bitter
orange juice inhibits cytochrome P450 3A4 (CYP3A4) metabolism of felodipine (7029).
INDINAVIR (Crixivan)
Interaction Rating = Moderate Be cautious with this combination.
Severity = Moderate • Occurrence = Possible • Level of Evidence = B
Bitter orange juice slightly increases indinavir levels, but this effect is likely to be clinically
insignificant. Bitter orange selectively inhibits intestinal cytochrome P450 3A4 (CYP3A4). The
metabolism of indinavir seems to be more dependent on hepatic CYP3A4 (11269). The effect
of bitter orange on other protease inhibitors has not been studied.
MIDAZOLAM (Versed)
Interaction Rating = Major Do not take this combination.
Severity = High • Occurrence = Probable • Level of Evidence = B
Bitter orange juice can significantly inhibit cytochrome P450 3A4 (CYP3A4) metabolism of
the midazolam, and potentially increase drug levels and adverse effects (7029).
MONOAMINE OXIDASE INHIBITORS (MAOIs)
Interaction Rating = Major Do not take this combination.
 Severity = High • Occurrence = Probable • Level of Evidence = D
Theoretically, concurrent use of MAOIs with synephrine-containing bitter orange
preparations might increase blood pressure raising effects of synephrine and potentially
cause hypertensive crisis. Bitter orange contains tyramine, octopamine, and synephrine,
which are MAO substrates (11267, 11995, 12378). Tell patients taking MAOIs to avoid using bitter
orange. Some MAOIs include phenelzine (Nardil), tranylcypromine (Parnate), and
others (2040).
QT INTERVAL-PROLONGING DRUGS
Interaction Rating = Moderate Be cautious with this combination.
Severity = High • Occurrence = Possible • Level of Evidence = D
Bitter orange in combination with other stimulants such as caffeine might prolong the QT
interval in some patients (13039). Theoretically, bitter orange could have an additive effect
when combined with drugs that prolong the QT interval and potentially increase the risk of
ventricular arrhythmias. Drugs that prolong the QT interval include amiodarone
(Cordarone), disopyramide (Norpace), dofetilide (Tikosyn), ibutilide (Corvert), procainamide
(Pronestyl), quinidine, sotalol (Betapace), thioridazine (Mellaril), and many others.
STIMULANT DRUGS
Interaction Rating = Moderate Be cautious with this combination.
Severity = Moderate • Occurrence = Possible • Level of Evidence = B
Theoretically, drugs with CNS stimulant properties, such as phenylpropanolamine,
pseudoephedrine, and caffeine, might increase the risk of hypertension and adverse
cardiovascular effects of bitter orange due to synephrine content (2040, 6979).
Interactions with Foods:
CAFFEINE: Theoretically, large amounts of caffeine-containing beverages might increase the
risk of hypertension and adverse cardiovascular effects with bitter orange. Bitter orange in
 
combination with caffeine can increase blood pressure and heart rate in otherwise healthy
normotensive adults (6979, 13657).
Interactions with Lab Tests:
AMPHETAMINE URINE DRUG SCREEN: Synephrine contained in bitter orange is chemically
similar to ephedrine, which has caused false positive urine amphetamine drug screens.
Theoretically, taking bitter orange products containing synephrine might cause a false-
positive for amphetamine on urine drug screen tests. However, one study shows that taking
  one dose of a specific bitter orange product (Nature's Way Bitter Orange, Springville, UT)
900 mg standardized to 6% synephrine did not cause a false positive on the CEDIA
Amphetamines Assay (91638).
GLUCOSE: Theoretically, bitter orange might reduce blood glucose concentrations and test
results in patients with type 2 diabetes (35751).
Interactions with Diseases or Conditions:
  DIABETES: Theoretically, bitter orange might interfere with blood sugar control in patients
with type 2 diabetes (35751); monitor blood sugar levels closely. 
HEADACHE: Headache has been reported as a side effect in some people taking bitter
orange products (14311). Theoretically, bitter orange might trigger headaches, including
migraine or cluster headache, due to its synephrine and octopamine content (11996). 
HYPERTENSION:Some studies suggest that bitter orange, especially in combination with
caffeine, can increase blood pressure in healthy people (13657, 13774); however, other research
has not found increased blood pressure in healthy adults (11268, 14311, 35753, 35764, 35770, 91681).
 The effects of bitter orange have not been studied in patients with existing hypertension.
Theoretically, bitter orange fruit, peel, or juice might worsen hypertension (2040, 6979). 
NARROW-ANGLE GLAUCOMA: Theoretically, bitter orange fruit, peel, or juice might worsen
narrow-angle glaucoma due to synephrine content (2040, 6979). 
LONG QT INTERVAL SYNDROME: Bitter orange in combination with other stimulants such as
caffeine might prolong the QT interval in some patients (13039). Theoretically, taking bitter
orange might increase the risk of ventricular arrhythmias in patients with long QT interval
syndrome. 
SURGERY: Bitter orange has stimulant effects. Theoretically, bitter orange might interfere
with surgical procedures by increasing heart rate and blood pressure. Tell patients to
discontinue bitter orange at least 2 weeks before elective surgical procedures. 
TACHYARRHYTHMIAS: Some studies suggest that bitter orange, especially in combination
with caffeine, can increase heart rate in healthy people (13657, 13774); however, other research
has not found increased heart rate in healthy adults (11268, 91681). The effects of bitter orange
have not been studied in patients with existing tachyarrhythmia. Theoretically, bitter orange
might worsen tachyarrhythmias (2040, 6979).
Dosage/Administration:
ORAL: For obesity or weight loss, bitter orange extract 975 mg in combination with St. John's
wort 900 mg and caffeine 528 mg per day has been used (11268). Another specific
combination product (Charge, Labrada) containing bitter orange 150 mg, providing 9 mg
synephrine, plus caffeine and several other ingredients taken twice daily has also been
 
used (15381); however, this product has not been shown to reduce weight.
Bitter orange extracts commonly contain from 1.5% to 6% synephrine (6969).
TOPICAL: For treatment of fungal skin infections, pure oil of bitter orange has been applied
once daily for 1-3 weeks (6972).
Editor's Comments:
The bitter orange tree is small and produces an extremely sour and bitter citrus fruit. It's
generally not considered an edible fruit, but it is eaten in Iran and Mexico (12193). Due to the
fruit's acidity it is popular for making marmalades and liquors such as triple sec, grand
marnier, cointreau, and curacao. The dried peel of the fruit is also used as a seasoning.
In Asian medicine, the entire dried unripe fruit is used primarily for digestive
disorders (12193). In Western countries the dried peel of the fruit has historically been used to
stimulate appetite. This is in surprising contrast to bitter orange's primary use today, as a
 
component of weight loss products. Bitter orange (synephrine) is considered a banned
substance by the National Collegiate Athletic Association (NCAA) (13163).
Bitter orange is frequently used in "ephedra-free" products since the FDA banned ephedra
in 2004 for serious adverse cardiovascular effects. Bitter orange and caffeine, a frequent
combination in weight loss and bodybuilding products, can cause hypertension and
increased heart rate in otherwise healthy normotensive adults. There is no evidence to
suggest that bitter orange is any safer than ephedra (13657).

This monograph was last reviewed on 09/05/2017 and last updated on 12/12/2017. Monographs are
reviewed and/or updated multiple times per month and at least once per year. If you have comments or
suggestions on something that should be reviewed or included, please tell the editors. For details about our
evidence-based approach, see our Editorial Principles and Process.
 

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