Bitter orange

Bitter orange/Drug Interactions:

  • Alpha-blockersAlpha-blockers: According to secondary sources, bitter orange might be antagonized by alpha-blocking agents.
  • AntiadrenergicsAntiadrenergics: Based on bitter orange's reported constituents, bitter orange may have adrenergic agonistic effects (44; 45; 46).
  • AntibioticsAntibiotics: According to secondary sources, bitter orange preparations have a variety of antimicrobial properties.
  • Antidepressant agents, monoamine oxidase inhibitors (MAOIs)Antidepressant agents, monoamine oxidase inhibitors (MAOIs): Preliminary research suggests that synephrine might have antidepressant effects (46; 47). Bitter orange contains tyramine, octopamine, and synephrine, which are MAO substrates (48; 19; 49; 50).
  • Antidiabetic agentsAntidiabetic agents: In human research, a tea containing Rauwolfia vomitoria and bitter orange fruit reduced two-hour postprandial glucose and HbA1c (51). In human research, Ripped Fuel Extreme Cut? containing 21mg of synephrine and 304mg of caffeine increased levels of postprandial glucose (35).
  • Antifungal agentsAntifungal agents: In human research, bitter orange oil had antifungal effects (22).
  • AntihelminthicsAntihelminthics: According to secondary sources, bitter orange may interact with antihelminthic agents.
  • AntihypertensivesAntihypertensives: In human research, systolic blood pressure, diastolic blood pressure, and/or heart rate increased in some (33; 34) but not all (38; 39; 40; 41; 42; 43) studies. Increased diastolic, but not systolic, blood pressure or heart rate occurred in a clinical trial involving Ripped Fuel Extreme Cut? containing 21mg of synephrine and 304mg of caffeine (35). In animal research, very high doses of bitter orange extract (6% synephrine) or 95% pure synephrine (a total of 10 or 50mg/kg of synephrine, respectively) resulted in increased heart rate and blood pressure; the bitter orange extract had the greater effect (36; 37).
  • Anti-inflammatory agentsAnti-inflammatory agents: In animal research, bitter orange peel had anti-inflammatory effects (73).
  • Antineoplastic agentsAntineoplastic agents: In laboratory research, bitter orange constituents auraptene, marmin, tangeretin, nobiretin, and a psoralen compound had antitumor effects (8).
  • Antiobesity agentsAntiobesity agents: In an animal toxicity study, p-synephrine resulted in a decrease in body weight gain (60). In human research, 50mg of p-synephrine from bitter orange extract (Advantra Z?) increased the resting metabolic rate vs. baseline resulting in an increase of consumption of 65kcal (twofold); however, significance vs. placebo and baseline was lacking (38).
  • AntiparasiticsAntiparasitics: According to secondary sources, bitter orange may interact with antiparasitic agents.
  • Antiviral agentsAntiviral agents: In laboratory research, bitter orange fruit had antiviral activity against rotavirus (14).
  • AnxiolyticsAnxiolytics: In human research, use of a Citrus aurantium blossom distillate prior to surgery improved scores on the State-Trait Anxiety Inventory (STAI-state) scale and the Amsterdam Preoperative Anxiety and Information Scale (APAIS) (57).
  • Beta-blockersBeta-blockers: According to secondary sources, concomitant use of bitter orange and beta-blockers may cause acute hypertension.
  • CaffeineCaffeine: Large amounts of caffeine may increase the risk of hypertension and adverse cardiovascular effects with bitter orange due to synephrine content (65). In animal research, very high doses of bitter orange extract (6% synephrine) or 95% pure synephrine (total of 10 or 50mg/kg synephrine, respectively) resulted in increased heart rate and blood pressure; the bitter orange extract had the greater effect (36; 37), and the addition of caffeine increased these effects; the effects on heart rate were suggested as being mainly due to caffeine in one of the included studies (37).
  • Cardiovascular agentsCardiovascular agents: In human research (clinical trials and case reports), tachycardia, tachyarrhythmia, QT prolongation, ischemic stroke, myocardial infarction, variant angina, and masked bradycardia and hypotension have been noted with use of bitter orange- or synephrine-containing multi-ingredient products (24; 25; 26; 27; 28; 29; 30; 31). In animal research, bitter orange caused vasoconstriction and increased mean arterial pressure (MAP) but reduced portal pressure (11) and bitter orange, standardized to 4-6% synephrine, demonstrated cardiovascular toxicity in rats, including ventricular arrhythmias with enlargement of QRS complex and mortality (32). According to secondary sources, adverse effects associated with synephrine-containing compounds included acute lateral-wall myocardial infarction, exercise-induced syncope, stroke, vasospasm and vasoconstriction, thrombosis, and ventricular fibrillation.
  • CNS stimulantsCNS stimulants: Theoretically, drugs with CNS stimulant properties, such as phenylpropanolamine and pseudoephedrine, may increase the risk of hypertension and adverse cardiovascular effects of bitter orange due to synephrine content (65).
  • Cytochrome P450-modifying agentsCytochrome P450-modifying agents: Bitter orange juice may inhibit cytochrome P450 3A4 (CYP3A4) metabolism of drugs (52), causing increased drug levels and potentially increasing the risk of adverse effects. However, the extent of bitter orange's effect on drug interactions is unknown. Bitter orange has been shown to selectively inhibit intestinal CYP3A4, but not hepatic CYP3A4 (53; 52). Its effect on p-glycoprotein, which strongly overlaps with CYP3A4 interactions, is unclear (53; 52; 74; 75). According to a review, Seville orange juice caused clinically significant interactions with cytochrome P4503A (CYP3A) (76). In human research, a combination product lacked effect on CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activity (77).
  • DecongestantsDecongestants: According to secondary sources, bitter orange may interact in combination with decongestant-containing cold preparations.
  • Dermatologic agentsDermatologic agents: Adverse effects to bitter orange- or synephrine-containing products have included photosensitivity, particularly in fair-skinned people (54), and topical application with bitter orange essential oil resulted in irritation (22).
  • Gastrointestinal agentsGastrointestinal agents: In a case report, ischemic colitis was associated with use of a bitter orange-containing dietary weight loss supplement (56). Bitter orange pills (Zhizhu? pills) containing Citrus aurantium L. were found to be more effective for symptoms of dyspepsia than the same pills containing Citrus sinensis in individuals with functional dyspepsia associated with spleen deficiency and qi-stagnation syndrome (58).
  • InsecticidesInsecticides: According to laboratory research, bitter orange peel oil had insecticidal effects (13).
  • Musculoskeletal agentsMusculoskeletal agents: According to case reports, adverse effects to bitter orange- or synephrine-containing products have included unsteady gait (28) and severe exercise-induced rhabdomyolysis (55).
  • Neurologic agentsNeurologic agents: Dizziness, difficulty in concentrating, memory loss, syncope, seizure, and stroke have been noted in case reports (28; 26). Theoretically, bitter orange may trigger migraine or cluster headache due to its synephrine and octopamine content (32).
  • Ophthalmic agentsOphthalmic agents: Theoretically, bitter orange may worsen narrow-angle glaucoma due to its synephrine content (19; 32).
  • Photosensitizing agentsPhotosensitizing agents: Adverse effects to bitter orange- or synephrine-containing products have included photosensitivity, particularly in fair-skinned people (54). According to secondary sources, oil of bergamot, from Citrus aurantium ssp. bergamia, may cause hyperpigmentation, dermatitis, or make a patient more sensitive to laser treatment. Bitter orange oil also contains the furocoumarins bergapten and oxypeucedanin, which have been shown to be photosensitizing (78).
  • PsoralensPsoralens: In laboratory research, bitter orange constituents auraptene, marmin, tangeretin, nobiretin, and a psoralen compound had antitumor effects (8). According to secondary sources, bitter orange may interact with psoralen agents.
  • QT-prolonging drugsQT-prolonging drugs: In a case report, a bitter orange-containing product prolonged the QT interval (26).
  • Respiratory agentsRespiratory agents: According to secondary sources, synephrine may cause relaxation of bronchial muscle.
  • Thyroid hormonesThyroid hormones: According to secondary sources, bitter orange may worsen overactive thyroid due to its synephrine content.
  • VasoconstrictorsVasoconstrictors: According to secondary sources, bitter orange may interact with vasoconstrictors.

    • Bitter orange/Herb/Supplement Interactions:

  • Antiadrenergic herbs and supplementsAntiadrenergic herbs and supplements: Based on bitter orange's reported constituents, bitter orange may have adrenergic agonistic effects (44; 45; 46).
  • AntibacterialsAntibacterials: According to secondary sources, bitter orange preparations have a variety of antimicrobial properties.
  • Antidepressant agents, monoamine oxidase inhibitors (MAOIs)Antidepressant agents, monoamine oxidase inhibitors (MAOIs): Preliminary research suggests that synephrine might have antidepressant effects (46; 47). Bitter orange contains tyramine, octopamine, and synephrine, which are MAO substrates (48; 19; 49; 50).
  • Antifungal agentsAntifungal agents: In human research, bitter orange oil had antifungal effects (22).
  • AntihelminthicsAntihelminthics: According to secondary sources, bitter orange may interact with antihelminthic herbs and supplements.
  • Anti-inflammatory agentsAnti-inflammatory agents: In animal research, bitter orange peel had anti-inflammatory effects (73).
  • Antineoplastic agentsAntineoplastic agents: In laboratory research, bitter orange constituents auraptene, marmin, tangeretin, nobiretin, and a psoralen compound had antitumor effects (8).
  • Antiobesity agentsAntiobesity agents: In an animal toxicity study, p-synephrine resulted in a decrease in body weight gain (60). In human research, 50mg of p-synephrine from bitter orange extract (Advantra Z?) increased the resting metabolic rate vs. baseline resulting in an increase of consumption of 65kcal (twofold); however, significance vs. placebo and baseline was lacking (38).
  • AntioxidantsAntioxidants: According to secondary sources, bitter orange may interact with antioxidant herbs and supplements.
  • AntiparasiticsAntiparasitics: According to secondary sources, bitter orange may interact with antiparasitic agents.
  • Antiviral agentsAntiviral agents: In laboratory research, bitter orange fruit had antiviral activity against rotavirus (14).
  • AnxiolyticsAnxiolytics: In human research, use of a Citrus aurantium blossom distillate prior to surgery improved scores on the State-Trait Anxiety Inventory (STAI-state) scale and the Amsterdam Preoperative Anxiety and Information Scale (APAIS) (57).
  • CaffeineCaffeine: Large amounts of caffeine may increase the risk of hypertension and adverse cardiovascular effects with bitter orange due to synephrine content (65). In animal research, very high doses of bitter orange extract (6% synephrine) or 95% pure synephrine (total of 10 or 50mg/kg synephrine, respectively) resulted in increased heart rate and blood pressure; the bitter orange extract had the greater effect (36; 37), and the addition of caffeine increased these effects; the effects on heart rate were suggested as being mainly due to caffeine in one of the included studies (37).
  • Cardioactive agentsCardioactive agents: In human research (clinical trials and case reports), tachycardia, tachyarrhythmia, QT prolongation, ischemic stroke, myocardial infarction, variant angina, and masked bradycardia and hypotension have been noted with use of bitter orange- or synephrine-containing multi-ingredient products (24; 25; 26; 27; 28; 29; 30; 31). In animal research, bitter orange caused vasoconstriction and increased mean arterial pressure (MAP) but reduced portal pressure (11), and bitter orange, standardized to 4-6% synephrine, demonstrated cardiovascular toxicity in rats, including ventricular arrhythmias with enlargement of QRS complex and mortality (32). According to secondary sources, adverse effects associated with synephrine-containing compounds included acute lateral-wall myocardial infarction, exercise-induced syncope, stroke, vasospasm and vasoconstriction, thrombosis, and ventricular fibrillation.
  • Cytochrome P450-modifying agentsCytochrome P450-modifying agents: Bitter orange juice may inhibit cytochrome P450 3A4 (CYP3A4) metabolism of drugs (52), causing increased drug levels and potentially increasing the risk of adverse effects. However, the extent of bitter orange's effect on drug interactions is unknown. Bitter orange has been shown to selectively inhibit intestinal CYP3A4, but not hepatic CYP3A4 (53; 52). Its effect on p-glycoprotein, which strongly overlaps with CYP3A4 interactions, is unclear (53; 52; 74; 75). According to a review, Seville orange juice caused clinically significant interactions with cytochrome P4503A (CYP3A) (76). In human research, a combination product lacked effect on CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activity (77).
  • DecongestantsDecongestants: According to secondary sources, bitter orange may interact in combination with decongestant-containing cold preparations.
  • FlavonoidsFlavonoids: In human research, a combination of naringin, hesperidin, and p-synephrine resulted in small, clinically insignificant changes in heart rate vs. synephrine alone (41).
  • Gastrointestinal agentsGastrointestinal agents: In a case report, ischemic colitis was associated with use of a bitter orange-containing dietary weight loss supplement (56). Bitter orange pills (Zhizhu? pills) containing Citrus aurantium L. were found to be more effective for symptoms of dyspepsia than the same pills containing Citrus sinensis in individuals with functional dyspepsia associated with spleen deficiency and qi-stagnation syndrome (58).
  • HoneyHoney: According to human research, honey may reduce the absorption of naringin, a flavone glycoside of bitter orange (79).
  • HypoglycemicsHypoglycemics: In human research, a tea containing Rauwolfia vomitoria and bitter orange fruit reduced two-hour postprandial glucose and HbA1c (51). In human research, Ripped Fuel Extreme Cut? containing 21mg of synephrine and 304mg of caffeine increased levels of postprandial glucose (35).
  • HypotensivesHypotensives: In human research, systolic blood pressure, diastolic blood pressure, and/or heart rate increased in some (33; 34) but not all (38; 39; 40; 41; 42; 43) studies. Increased diastolic, but not systolic, blood pressure or heart rate occurred in a clinical trial involving Ripped Fuel Extreme Cut? containing 21mg of synephrine and 304mg of caffeine (35). Very high doses of bitter orange extract (6% synephrine) or 95% pure synephrine (total of 10 or 50mg/kg of synephrine, respectively) resulted in increased heart rate and blood pressure; the bitter orange extract had the greater effect (36; 37).
  • InsecticidesInsecticides: According to laboratory research, bitter orange peel oil had insecticidal effects (13).
  • Musculoskeletal agentsMusculoskeletal agents: According to case reports, adverse effects to bitter orange- or synephrine-containing products have included unsteady gait (28) and severe exercise-induced rhabdomyolysis (55).
  • Neurologic agentsNeurologic agents: Dizziness, difficulty in concentrating, memory loss, syncope, seizure, and stroke have been noted in case reports (28; 26). Theoretically, bitter orange may trigger migraine or cluster headache due to its synephrine and octopamine content (32).
  • Ophthalmic agentsOphthalmic agents: Theoretically, bitter orange may worsen narrow-angle glaucoma due to its synephrine content (19; 32).
  • Panax ginsengPanax ginseng: Theoretically, Panax ginseng might prolong the QT interval on electrocardiogram (ECG). Theoretically, combining Panax ginseng and bitter orange might have an additive effect on the QT interval and may increase the risk for arrhythmias (80; 81).
  • Photosensitizing agentsPhotosensitizing agents: Adverse effects from bitter orange- or synephrine-containing products have included photosensitivity, particularly in fair-skinned people (54). According to secondary sources, oil of bergamot, from Citrus aurantium ssp. bergamia, may cause hyperpigmentation or dermatitis, or make a patient more sensitive to laser treatment. Bitter orange oil also contains the furocoumarins bergapten and oxypeucedanin, which have been shown to be photosensitizing (78).
  • PsoralensPsoralens: In laboratory research, bitter orange constituents auraptene, marmin, tangeretin, nobiretin, and a psoralen compound had antitumor effects (8). According to secondary sources, bitter orange may interact with psoralen agents.
  • Radioprotective agentsRadioprotective agents: According to secondary sources, bitter orange may interact with radioprotective herbs and supplements.
  • Renally eliminated agentsRenally eliminated agents: According to secondary sources, bitter orange may interact with renally eliminated herbs and supplements.
  • Respiratory agentsRespiratory agents: According to secondary sources, synephrine may cause relaxation of bronchial muscle.
  • StimulantsStimulants: Theoretically, herbs and supplements with CNS stimulant properties, such as cola nut, ephedra, guarana, and mate, might increase the risk of hypertension and adverse cardiovascular effects of bitter orange due to synephrine content (65).
  • VasoconstrictorsVasoconstrictors: According to secondary sources, bitter orange may interact with vasoconstrictors.

    • Bitter orange/Alternative Therapy Interactions:

  • Auricular acupressureAuricular acupressure: Following consumption of Citrus aurantium L. extracts, naringenin and hesperetin increased in the plasma; auricular acupressure increased the levels of these flavanones following consumption of the extract (82).

    • Bitter orange/Food Interactions:

  • Citrus fruitsCitrus fruits: According to secondary sources, citrus juices and marmalades contain p-synephrine.
  • Caffeine-containing foodsCaffeine-containing foods: Large amounts of caffeine may increase the risk of hypertension and adverse cardiovascular effects with bitter orange due to synephrine content (65). In animal research, very high doses of bitter orange extract (6% synephrine) or 95% pure synephrine (total of 10 or 50mg/kg synephrine, respectively) resulted in increased heart rate and blood pressure; the bitter orange extract had the greater effect (36; 37), and the addition of caffeine increased these effects; the effects on heart rate were suggested as being mainly due to caffeine in one of the included studies (37).
  • HoneyHoney: Honey may reduce the absorption of naringin, a flavone glycoside of bitter orange (79).

    • Bitter orange/Lab Interactions:

  • Blood glucoseBlood glucose: In human research, a tea containing Rauwolfia vomitoria and bitter orange fruit reduced two-hour postprandial glucose and HbA1c (51). In human research, Ripped Fuel Extreme Cut? containing 21mg of synephrine and 304mg of caffeine increased levels of postprandial glucose (35).
  • Blood pressureBlood pressure: In human research, systolic blood pressure, diastolic blood pressure, and/or heart rate increased in some (33; 34) but not all (38; 39; 40; 41; 42; 43) studies. Increased diastolic, but not systolic, blood pressure or heart rate occurred in a clinical trial involving Ripped Fuel Extreme Cut? containing 21mg of synephrine and 304mg of caffeine (35). Very high doses of bitter orange extract (6% synephrine) or 95% pure synephrine (total of 10 or 50mg/kg synephrine, respectively) resulted in increased heart rate and blood pressure; the bitter orange extract had the greater effect (36; 37).
  • Thyroid hormone levelsThyroid hormone levels: According to secondary sources, bitter orange may worsen overactive thyroid due to its synephrine content.