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Bitter Orange

Scientific Name(s): Citrus aurantium L.
Common Name(s): Bigarade, Bitter orange, Bitter orange flower, Bitter orange peel, Green orange, Kijitsu, Laranja-amarga, Laranja-azeda, Laranja-cavalo, Neroli flowers, Neroli oil, Seville orange, Shangzhou zhiqiao, Sour orange, Zhi qiao, Zhi shi

Clinical Overview

Use

Pharmacological actions for C. aurantium include antispasmodic, sedative, demulcent, digestive, tonic, and vascular stimulant; as an anti-inflammatory, antibacterial, and antifungal agent; and for reducing cholesterol. Clinical data are limited. Most medical literature focuses on the plant's safety and efficacy in OTC weight loss supplement formulations, with studies using small sample sizes and often focusing on combination products. Therefore, no recommendations for any indication can be made.

Dosing

Follow manufacturer's dosage guidelines because synephrine content may vary in supplement formulations.

Contraindications

Because of potentially additive effects, avoid synephrine use in patients with hypertension, tachyarrhythmia, hyperthyroidism, or narrow-angle glaucoma.

Pregnancy/Lactation

Avoid use. Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

C. aurantium inhibits intestinal CYP3A4 and intestinal efflux in the small intestine and may interact with numerous drugs, including amiodarone, anxiolytics, antidepressants, antiviral agents, calcium channel blockers, dextromethorphan, GI prokinetic agents, vasoconstrictors, and weight loss formulas.

Adverse Reactions

Bitter orange may cause photosensitization, particularly in people with fair skin. There are numerous case reports of adverse cardiac reactions associated with C. aurantium extract use.

Toxicology

Bitter orange is considered generally recognized as safe (GRAS) by the US Food and Drug Administration (FDA) when consumed in amounts found in foods. 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.

Botany

In addition to the hybrid C. aurantium, many varieties and subspecies have been described. Bitter orange includes the varieties amara, bergamia, bigaradia, and vulgaris Risso. It is also known as Aurantii pericarpium in pharmaceutical Latin. Bitter orange probably originated in Southeast Asia. During the 10th and 11th centuries, traders introduced the plant to several Mediterranean regions and it was widely cultivated. The plant 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, gland-dotted 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 compared with other citrus trees.1, 2, 3, 4, 6, 7, 8, 9

History

The Spanish and Portuguese brought bitter orange to the Americas in the 1500s. In Europe, bitter orange flowers and oil have been used as sedatives and as prophylactics 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 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, 10 In modern times, the Chinese use "zhi shi" for its positive inotropic effects, particularly for treating shock.11 In Brazilian folk medicine, bitter orange was used as an anticonvulsant and to treat anxiety and insomnia.12 Uses in the United States have included prevention of skin, breast, and colon cancer. In Haiti, the plant has been used as an antiseptic and purgative; in Turkey, it has been used as a narcotic, sedative, and as 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.13

Bitter orange oil is used 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

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.13 On April 11, 2004, the FDA banned the sale of dietary supplements containing ephedrine alkaloids because of 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 are closely monitored.10

Chemistry

A number of phytochemicals of medicinal interest have been found in the plant, including in the leaf, flower, fruit, seeds, and peel.13, 14

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 tetranortriterpenoids (limonin).1, 15, 16, 17

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. Synephrine, 5,8-epidioxyergosta-6,22-dien-3 beta-ol, adenosine, asparagine, tyrosine, valine, isoleucine, alanine, beta-sitosterol, and beta-daucosterol are also found in the flowers.1, 15, 18

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.19, 20

Seeds

17-beta-D-glucopyranosides have been isolated from the seeds.21, 22

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, and C; and carotenoid pigments.1, 15, 23

Additional coumarin glycosides have also been isolated from C. aurantium.24, 25

Numerous weight loss products contain adrenergic amines structurally similar to ephedrine alkaloids, including synephrine, octopamine, tyramine, N-methyltyramine, and hordenine.26 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.27

There are 6 possible isomers of synephrine and disagreement as to whether bitter orange contains para-synephrine, meta-synephrine, or both.27 The distinction is important because there are potential differences in 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. The Canadian government has enacted dosage and usage restrictions for the para-synephrine alkaloid of C. aurantium. 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.26, 28

Uses and Pharmacology

There are numerous pharmacological actions recognized for C. aurantium. The leaf and flower have been studied for anticancer activity and as antispasmodics and sedatives. The peel has been studied as a digestive aid, demulcent, tonic, and vascular stimulant; as an anti-inflammatory, antibacterial, and antifungal agent; and for reducing cholesterol.1, 15

The most current literature focuses on the plant's safety and efficacy in OTC weight loss supplement formulations in which synephrine content may vary. Manufacturer dosage guidelines should be followed.

Anxiety

In vitro/animal data

In mice, the anxiolytic and sedative effects of bitter orange extract 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 The anxiolytic effects may be attributed to C. aurantium's effects on 5-HT1A receptors.29

Clinical data

In a study of 60 patients undergoing surgery, pretreatment with 1 mL/kg of C. aurantium blossom reduced preoperative anxiety, as noted by reductions in State-Trait Anxiety Inventory and Amsterdam Preoperative Anxiety and Information Scale scores. These parameters remained unchanged in the control group.30 State- and trait-anxiety scores were observed to be statistically significantly improved with administration of bitter orange compared to placebo, but not significantly different to that of lavender, in 156 postmenopausal women enrolled in a triple-blind, randomized, controlled trial. At week 8, adjusted mean state- and trait-anxiety scores were each reduced by 4% compared to controls. The side effect that was higher with bitter orange than placebo was palpitations (4.2% vs 2.1%, respectively) Bitter orange capsules contained 500 mg whole dried herb (limonene 20%, linalool 32%, flavonoid 5%), no volatile oils, and were taken twice daily.67

In a randomized study of pregnant women, gauzes soaked in C. aurantium applied to the collar every 30 minutes during labor were found to decrease anxiety at 3 to 4 cm dilation (P < 0.001) and at 6 to 8 cm dilation (P < 0.001) compared with controls.31

Dementia

C. aurantium extract was found to improve learning and memory impairment caused by scopolamine in rats.47

Depression

In mice, para-synephrine may have antidepressant activity, as documented by immobility tests.44 The antidepressant effects may be greater with the S isomer of para-synephrine.45

Effects on glucose

p-Synephrine was found to reduce glucose suppression as well as glucose-6-phosphatase and phosphoenol pyruvate carboxykinase levels in H4IIE rat liver cells.46

Labor pains

In a randomized, open-label study of primiparous women, gauzes soaked in C. aurantium applied to the collar every 30 minutes during labor were found to decrease pain severity at 3 to 4 cm dilation (P < 0.05), 5 to 7 cm dilation (P < 0.05), and 8 to 10 cm dilation (P < 0.05) compared with controls.48

Liver Injury

5-hydroxy-6,7,3’,4’-tetramethoxyflavone and limonexic acid, compounds derived from C. aurantium, were found to exert protective effects against carbon tetrachloride-induced liver injury as tested in human HL-7702 cells.49

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.14, 26, 27, 32, 33, 34

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.13, 26

In a study of rats, the combination of C. aurantium 5.6 mg/kg with Rhodiola rosea 20 mg/kg was found to cause feeding suppression as well as visceral fat reduction, but not body weight reduction. The combination also caused a decrease in plasma norepinephrine levels.35

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 dietary counseling. Outcomes were measured at baseline and 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 regarding changes in cardiovascular activity or adverse reactions.8, 34, 36 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.37

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 (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.38 Another clinical trial in 18 subjects documented no changes in the QT interval or blood pressure after a single oral dose of 27 mg of meta-synephrine or para-synephrine.39

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 (C. aurantium alone [synephrine 45 mg] or a multicomponent supplement containing synephrine 5.5 mg), with a 1-week washout period between treatments. 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 by other stimulants in the supplement.40 The same research team documented similar cardiovascular stimulant activity in another study in 10 healthy normotensive adults.41 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.42

A 60-day, double-blind, placebo-controlled safety study (n = 67 evaluable) was conducted in moderately overweight adults (mean body mass index, 30.8). The 3 treatment assignments were p-synephrine 24.4 mg (Advantra Z), a combination product (p-synephrine 24.6 mg plus hesperidin 50.1 mg plus naringin 288 mg), or placebo; participants were instructed to take 1 capsule twice daily. Compared with baseline, there were no differences among the 3 groups for any blood chemistry changes, including lipid profiles, liver enzymes, serum electrolytes, and complete blood counts. No differences were seen among the 3 groups for systolic or diastolic blood pressure compared with baseline. The placebo group experienced a significant reduction from baseline in heart rate compared with each of the active treatments (P = 0.01); heart rate in the p-synephrine group was significantly lower than with the combination product (P = 0.01). No data were provided on body weight changes, and no serious adverse reactions were seen.43

Dosing

Follow manufacturer's dosage guidelines because synephrine content may vary in supplement formulations. There is evidence of effective weight loss at a synephrine dose of 32 mg/day, and doses up to 80 mg/day have been used for treatment of obesity.5, 26, 33 Another reference suggests 4 to 6 g of dried peel (C. aurantium) administered as a tea.9

Pregnancy / Lactation

Avoid use. Information regarding safety and efficacy in pregnancy and lactation is lacking.13 In a study of rats, there were no developmental toxicities with synephrine doses up to 100 mg/kg.50

Interactions

C. aurantium inhibits intestinal CYP3A4 and intestinal efflux (P-glycoprotein) in the small intestine and may interact with numerous drugs.5

Amiodarone

In a study of rats, the peak plasma concentration (Cmax) of amiodarone (50 mg/kg on day 15) was increased in rats pretreated with C. aurantium 164 mg/kg/day for 14 days. However, the amount of systemic exposure to amiodarone was similar between pretreated and control rats.51

Antivirals

In an open-label, crossover study in 13 healthy volunteers, subjects received indinavir 800 mg every 8 hours for 1 day and a single 800 mg dose the next morning with 240 mL of water or Seville orange juice.52 Compared with water, taking indinavir with Seville orange juice prolonged the time to reach the indinavir Cmax by 50% (from 1.25 to 1.87 hours). This change is not likely to be clinically important.

Anxiolytics and antidepressants

Bitter orange may increase the adverse reactions of these medications.

Calcium channel blockers

In a randomized, crossover study involving 10 healthy volunteers taking a felodipine 10 mg extended-release tablet with 240 mL of Seville orange juice, the area under the curve and Cmax of felodipine increased 76% and 61%, respectively, compared with felodipine taken with water.53

Dextromethorphan

In a study of 11 healthy volunteers, dextromethorphan 30 mg taken with 200 mL of Seville orange juice increased the bioavailability of dextromethorphan from 0.1 to 0.46 compared with dextromethorphan taken with water.54

GI prokinetic agents, vasoconstrictors, and weight loss formulas

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

Adverse Reactions

Bitter orange may cause photosensitization, particularly in people with fair skin.5, 11 Numerous case reports of adverse reactions and events associated with bitter orange have been reported to the FDA; however, many of the cases occurred with dietary supplements containing bitter orange in combination with other products, such as caffeine, making the cause and association more difficult to determine, particularly in cases of cardiovascular adverse reactions.55, 56 A review of the literature found that p-synephrine alone or in combination with other products did not increase heart rate or blood pressure but did increase resting metabolic rate and energy expenditure.57

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 notable medical history or atherosclerotic risk factors and took no medications. Other possible causes of ischemic stroke proved to be unlikely.58

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.59

Another case report documented 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 22-year-old male experienced a non-ST–elevation myocardial infarction following 3 weeks of ingesting 2 dietary supplements containing C. aurantium and 1,2-dimethylamylamine, among other ingredients, daily prior to exercise. He had no family history of early coronary artery disease or sudden death. Upon treatment and discontinuation of the supplement, he was symptom free with no evidence of ischemia.28

A 28-year-old man suffered a massive myocardial infarction after abusing synephrine tablets (dose not provided).13

There is also a case report of variant angina occurring with bitter orange.60

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.61

Toxicology

Bitter orange is considered GRAS by the FDA when consumed in amounts found in foods.5

Animal studies document the potential cardiac toxicity. N-methyltyramine increased renal and cerebral resistance in dogs. Additionally, synephrine induced dose-dependent portal hypotensive effects and ventricular arrhythmias with enlargement of QRS complex in rats.6, 32, 62, 63, 64

C. aurantium contains the stimulant amines synephrine, octopamine, and N-methyltyramine.65 These amines may cause vasoconstriction as well as increased heart rate and blood pressure. Sympathomimetics also cause resistant hypertension.66

Because of potentially additive effects, avoid synephrine use in patients with hypertension, tachyarrhythmia, hyperthyroidism, or narrow-angle glaucoma.

An overdose of synthetic synephrine in children caused nausea, vomiting, irritation, tachycardia, and a rapid increase in blood pressure.13

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