Bitter Orange

December 2007

Citrus aurantium L. Family: Rutaceae

Bitter orange , bitter orange flower , bitter orange peel , green orange , kijitsu , neroli oil , Seville orange , shangzhou zhiqiao , sour orange , bigarade , neroli flowers , laranja-amarga , laranja-azeda , laranja-cavalo , zhi shi , zhi qiao ^1, , ^2, , ^3, , ⁴

Uses

Pharmacological actions for C. aurantium include the following: antispasmodic, sedative, tranquilizer, cholagogue, demulcent, eupeptic, tonic, and vascular stimulant; as an anti-inflammatory, antibacterial, and antifungal agent; and for reducing cholesterol; however, clinical data is limited. Most medical literature focuses on the safety and efficacy of its use in over-the-counter weight-loss supplement formulations. Studies examining this use have used small sample sizes and often focus on combination products.

Dosing

Follow manufacturer's dosage guidelines because synephrine content may vary in supplement formulation. There is evidence of effective weight loss at a synephrine dose of 32 mg/day in treating obesity.

Contraindications

Because of the potential for additive effects, synephrine use is best avoided in patients with hypertension, tachyarrhythmia, or narrow angle glaucoma.

Pregnancy/Lactation

Avoid use due to lack of clinical data regarding safety and efficacy during pregnancy and lactation.

Interactions

Bitter orange may inhibit intestinal CYP3A4 and intestinal efflux and may interact with numerous drugs, including anxiolytics, antidepressants, antiviral agents, calcium channel blockers, dextromethorphan, GI prokinetic agents, vasoconstrictors, and weight-loss formulas.

Adverse Reactions

There are numerous case reports of adverse cardiac reactions associated with C. aurantium extract use.

Toxicology

Medical literature primarily documents cardiovascular toxicity, especially due to the stimulant amines synephrine, octopamine, and N-methyltyramine, which may cause vasoconstriction as well as increased heart rate and blood pressure.

In addition to C. aurantium , bitter orange may also be listed as C. aurantium amara , Citrus bergamia , Citrus bigaradia , Citrus vulgaris , or Aurantii pericarpium . Bitter orange probably originated from southeast Asia. During the 10th and 11th centuries, traders introduced the plant to several Mediterranean regions and it was widely cultivated. It is grown commercially in southern Europe, particularly in Spain and Portugal, as well as in Israel and various islands of the Caribbean. This evergreen tree grows up to 10 m in height and has long, leathery, dark green leaves and scented white flowers with 5 to 8 petals. The membranes and pulp of the orange fruit are bitter and sour. The tree is very resistant to plant diseases when compared with other citrus trees. ^1, , ^2, , ^5, , ^6, , ⁷

The Spanish and Portuguese brought bitter oranges to the Americas in the 1500s. In Chinese folk medicine, bitter orange was used as a tonic and carminative to treat dyspepsia. Dried bitter orange was used to treat ptosis of the uterus and anus, to relieve abdominal distention and diarrhea, and for blood in feces. ^1, , ⁸

In Europe, bitter orange flowers and oil have been used as a sedative and as a prophylactic for GI complaints, nervous conditions, gout, sore throat, and insomnia. The plant has been used to treat toxic and anaphylactic shock, heart conditions, cardiac exhaustion, and cancer. ^1, , ^3, In Brazilian folk medicine it was used as an anticonvulsant and to treat anxiety and insomnia. ⁹

Bitter orange oil is used extensively to flavor many food products, alcoholic and nonalcoholic beverages, frozen dairy desserts, candy, baked goods, gelatins and puddings, meat and meat products, and condiments and relishes. ¹

Its purported uses in the United States include prevention of skin, breast, and colon cancer. In Haiti the plant has been used as an antiseptic and purgative and in Turkey it has been used as a narcotic, sedative, and treatment for scurvy. The plant has been used as a remedy for treatment-resistant fungal skin diseases, and the tincture or extract has been used for treating heartburn. ¹⁰

Powdered extracts of the dried immature fruit or peel are used as an alternative to ephedra in many dietary supplements and herbal weight-loss products. ^10, On April 11, 2004, the Food and Drug Administration banned the sale of dietary supplements containing ephedrine alkaloids because of the safety concerns. Many manufacturers of weight-loss supplement formulations now offer ephedra-free products containing bitter orange extract. Because bitter orange extract contains a sympathomimetic, the safety and efficacy of these formulations is monitored closely. ⁸

A number of phytochemicals of medicinal interest have been found throughout the plant, including the leaf, flower, fruit, seeds, and peel. ^10, , ¹¹

Leaf The essential or volatile oil (0.2% to 0.4%) contains more than 90% monoterpene hydrocarbons, alcohols, flavonoid-glycosides, aldehydes, ketone-free acids, esters, coumarins, and tetranotriterpenoids (limonin). ^1, , ^12, , ^13, , ¹⁴

Flower The essential or volatile oil (0.05% to 0.5%) contains monoterpene hydrocarbons, alcohols, and flavonoid-glycosides similar to those contained in the leaf. The following constituents are also found in the flowers: synephrine, 5,8-epidioxyergosta-6,22-dien-3 β-ol, adenosine, asparagine, tyrosine, valine, isoleucine, alanine, β-sitosterol, and β-daucosterol. ^1, , ^12, , ¹⁵

Fruit The fruit contains octopamine, synephrine, and tyramine. Synephrine is the main chemical constituent in the fruit (0.1% to 0.35%). The fruit primarily contains the glycosylated flavanones naringin and neohesperidin. ^16, , ¹⁷

Seeds 17-β-D-glucopyranosides have been isolated from the seeds. ^18, , ¹⁹

Peel The essential or volatile oil (2%) contains monoterpene hydrocarbons (90% limonene), bitter and nonbitter flavonoids, furanocoumarins, flavonoid-glycosides, mineral salts, pectin, organic acids, vitamins (A, B₁ , C), and carotenoid pigments. ^1, , ^12, , ²⁰

Additional coumarin glycosides have also been isolated from C. aurantium . ^21, , ²²

Numerous weight-loss products contain adrenergic amines structurally similar to ephedrine alkaloids, including synephrine, octopamine, tyramine, N-methyltyramine, and hordenine. ^23, Some literature documents the importance of distinguishing the alkaloid constituents in bitter orange because of the potential alpha-adrenergic and beta-adrenergic activity, particularly para-synephrine versus meta-synephrine. ²⁴

There are 6 possible isomers of synephrine, with disagreement as to whether bitter orange contains para-synephrine, meta-synephrine, or both. ^24, The distinction is important because of the pharmacological properties that may affect safety and efficacy of commercial products. Para-synephrine occurs naturally in the human body, is an alpha-adrenergic agonist, and has some beta-adrenergic properties. Meta-synephrine (often referred to as phenylephrine), an isomer of para-synephrine, is also an alpha-adrenergic agonist and has some beta-adrenergic agonist properties. ²³

There are numerous pharmacological actions recognized for C. aurantium . The leaf and flower have been studied for anticancer activity and as an antispasmodic, sedative, and tranquilizer. The peel has been studied as a cholagogue, demulcent, eupeptic, tonic, and vascular stimulant, as well as an anti-inflammatory, antibacterial, and antifungal agent, and for reducing cholesterol. ^1, , ¹²

The most current literature focuses on the plant's safety and efficacy in over-the-counter weight-loss supplement formulations. Patients should be aware when taking over-the-counter formulations that synephrine content may vary and that manufacturer dosage guidelines should be followed.

Weight loss Synephrine alkaloids increase energy expenditure and decrease food intake through activation of alpha- and beta-adrenergic receptors. Synephrine alkaloids may also decrease food intake by reducing gastric motility. ^11, , ^23, , ^24, , ^25, , ^26, , ²⁷

Animal data Several studies have demonstrated that synephrine alkaloids reduce food intake and white fat cells in rats, hamsters, and dogs. Synephrine also promotes lipolysis in adipocytes through beta-adrenergic stimulation. ^10, , ²³

Clinical data In a 6-week, double-blind, placebo-controlled, randomized study, 23 subjects with body-mass indices more than 25 kg/m² were assigned to 1 of 3 groups. Group A received a mixture containing C. aurantium 975 mg (6% synephrine alkaloid), St. John's wort 900 mg (3% hypericin), and caffeine 528 mg; group B received a maltodextrin placebo; and group C was a control without placebo. All patients completed a 3 day/week exercise program and received American Heart Association's dietary counseling. Outcomes were measured at baseline as well as at 3 and 6 weeks and included changes in weight, percent body fat, fat mass, and basal metabolism. Patients in group A lost an average of 1.4 kg ( P < 0.05); group B lost an average of 0.9 kg ( P < 0.1); group C lost an average of 0.4 kg. No changes were noted in cardiovascular activity (ie, changes in laboratory tests, blood pressure, heart rate, or electrocardiograms). Reviewers of this study note that although the authors performed a statistical analysis of within-group changes in weight, they did not perform the same comparison among groups. No evidence was presented on changes in cardiovascular activity or adverse reactions. ^7, , ^27, , ^28, Another trial involving 15 subjects examined the cardiovascular effects of a single dose of a commercially available product containing bitter orange, standardized to 6% synephrine. Outcome measures included changes in systolic and diastolic blood pressure and heart rate measured at baseline and every hour for 6 hours after oral administration. Changes or increases were found in systolic and diastolic blood pressure and heart rate for up to 5 hours after administration of a single dose of synephrine. ²⁹

Changes in blood pressure and pulse were examined in 12 subjects in a randomized, open-label, placebo-controlled, crossover design study. Patients consumed either C. aurantium juice (contains synephrine 13 to 14 mg) or a water placebo. Blood pressure and pulse were measured hourly for 5 hours in patients who consumed the juice. It was determined that C. aurantium juice had no effects on blood pressure or pulse. ^30, Another clinical trial of 18 subjects documented no changes in the QT interval or blood pressure after a single oral dose of meta- or para-synephrine 27 mg. ³¹

Changes in cardiovascular activity (ie, systolic and diastolic pressure, heart rate) were examined in 10 subjects in a randomized, double-blind, placebo-controlled crossover study. Two commercial supplements were tested in patients, with a 1-week washout period between treatments: (1) C. aurantium alone (synephrine 45 mg); or (2) a multicomponent supplement containing synephrine 5.5 mg. Patients using the multicomponent drug supplement experienced clinical and statistical changes in cardiovascular activity. However, because an 8-fold higher dose of synephrine had no effect on blood pressure, it was concluded that the pressor effects were not caused by C. aurantium but were caused by other stimulants in the supplement. ^32, The same research team also documented similar cardiovascular stimulant activity in another study in 10 healthy, normotensive adults. ^33, A study examining the physiological effects of a multicomponent drug supplement containing synephrine 6 mg found no changes in 10 sedentary men with more than 20% body fat when evaluated at rest and during treadmill walking. ³⁴

Other pharmacologic activity

Anxiety In mice, anxiolytic and sedative effects of 0.5 to 1 g/kg extract of bitter orange were compared with chlordiazepoxide 10 mg/kg, valproic acid 400 mg/kg, or diazepam 1.2 mg/kg. Mice were treated orally with 1 g/kg of the extract. After 30 minutes, each animal was injected with sodium pentobarbital 40 mg/kg. Sedative effects were measured in seconds by induction time (time from injection to loss of rightness reflex) and duration of sleep (time from loss of rightness reflex to awakening). The extract significantly increased the hypnotic effect of pentobarbital ( P < 0.05). Several tests were used to examine the anxiolytic effect of the extract; however, the extract used in the elevated plus maze test produced an anxiolytic effect ( P < 0.05). ⁴

Depression In mice, para-synephrine may have antidepressant activity, as documented by immobility tests. ^35, The antidepressant effects may be greater with the S isomer of para-synephrine. ³⁶

Synephrine content of bitter orange products varies widely. Review manufacturers' dosage guidelines because of the numerous commercially available synephrine products. There is evidence for effective weight loss at a synephrine dose of 32 mg/day synephrine in treating obesity. ^23, , ²⁶

Avoid use due to lack of clinical data regarding safety and efficacy during pregnancy and lactation. ¹⁰

C. aurantium inhibits intestinal CYP3A4 and intestinal efflux (P-glycoprotein) in the small intestine and may interact with numerous drugs.

Anxiolytics and antidepressants Theoretically, bitter orange may increase the adverse reactions of these medications.

Antivirals In an open-label, crossover study in 13 healthy volunteers, subjects received indinavir 800 mg every 8 hours for 1 day and as a single 800 mg dose the next morning with 240 mL of water or Seville orange juice. ³⁷ Compared with water, taking indinavir with Seville orange juice prolonged the time to reach the indinavir peak plasma concentration 50% (from 1.25 to 1.87 hours). This change is not likely to be clinically important.

Calcium channel blockers In a randomized, crossover study involving 10 healthy volunteers, taking a felodipine extended-release 10 mg tablet with 240 mL of Seville orange juice increased the area under the plasma concentration-time curve and peak plasma concentration of felodipine 76% and 61%, respectively, compared with taking felodipine with water. ³⁸

Dextromethorphan In a study of 11 healthy volunteers, compared with water, taking dextromethorphan 30 mg with 200 mL of Seville orange juice increased the bioavailability of dextromethorphan from 0.1 to 0.46. ³⁹

GI prokinetic agents, vasoconstrictors, and weight-loss formulas Theoretically, bitter orange may increase the adverse reactions of these medications.

There are numerous case reports of adverse reactions associated with bitter orange.

Cardiovascular system A 38-year-old man suffered an ischemic stroke after taking a dietary supplement containing synephrine daily for 1 week. The patient had no medical history or atherosclerotic risk factors and took no medications. Other possible causes of ischemic stroke proved to be unremarkable. ⁴⁰

A 52-year old woman developed unremitting tachycardia after consuming a daily dose of C. aurantium extract 500 mg (synephrine 30 mg/day). She had been taking thyroxine 50 mcg/day for hypothyroidism for about 10 years. ⁴¹

Another case report documents a 55-year-old woman with an acute-lateral-wall myocardial infarction. The patient was taking a dietary supplement containing C. aurantium 300 mg for weight loss for 1 year. She had numerous risk factors for myocardial infarction. ⁴

A 28-year-old man suffered a massive myocardial infarction after abusing synephrine tablets (dose not provided). An overdose of synthetic synephrine in children caused nausea, vomiting, irritation, tachycardia, and a rapid increase in blood pressure. ¹⁰

There is also a case report on variant angina with bitter orange. ⁴²

Muscular system A 22-year-old man developed rhabdomyolysis after consuming a synephrine-containing weight-loss formula. While exercising, the patient developed fatigue, dehydration, and myalgias. ⁴³

Animal studies document the following potential cardiac toxicity: N-methyltyramine increased renal and cerebral resistance in dogs; synephrine induced dose-dependent portal hypotensive effects and ventricular arrhythmias with enlargement of QRS complex in rats. ^5, , ^25, , ^44, , ^45, , ⁴⁶

C. aurantium contains the stimulant amines synephrine, octopamine, and N-methyltyramine. ^47, These amines may cause vasoconstriction as well as increased heart rate and blood pressure. Sympathomimetics also cause resistant hypertension. ⁴⁸

Because of the potential for additive effects, synephrine use should be avoided in patients with hypertension, tachyarrhythmia, or narrow-angle glaucoma.

Ephedrine and synephrine are banned by many sports agencies. A single dose of a commercially available synephrine product did not cause a false-positive response in an amphetamine assay. ⁴⁹

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