Bitter orange

    Researchedby:
    Sara Gardy, Sarah Schriewer

    Fact-checked

    by:

    Marina Shkayeva, Gregory Lopez
    Last Updated: July 10, 2023

    A molecule that is similar to ephedrine in mechanism, but less potent. Commonly referred to as "bitter orange", synephrine appears to be a less potent fat-burner relative to ephedrine. It may exert some minor health effects on digestion and circulation.

    What is bitter orange?

    Bitter orange, also known as Citrus aurantium, is a citrus fruit originally used in Traditional Chinese medicine for stomach ailments, such as constipation, diarrhea, and indigestion.[1] Today, bitter orange extract, standardized to p-synephrine content, commonly occurs in multi-ingredient formulations labeled as ephedra-free supplements for weight loss: p-synephrine is an alkaloid compound structurally similar to adrenaline and the banned dietary supplement ephedrine.[2] The pharmacologic and pharmacokinetic properties of p-synephrine vary from its structural analogues enough to mitigate the risks previously seen with ephedrine-containing supplements. [1]. p-synephrine should also not be confused with m-synephrine, a synthetic amine derivative of synephrine. m-synephrine does not meet the FDA dietary supplement definition and is a prohibited ingredient.

    Is bitter orange considered a performance-enhancing supplement for athletes?

    What are bitter orange’s main benefits?

    There is interest in using bitter orange for weight loss and improvement in body composition (fat loss). However, this is not supported by clinical data.[3] Bitter orange is also used for athletic performance, but its benefit is not clear.[4]

    One study found that applying bitter orange oil 20–25% to affected skin for 1 to 3 weeks was associated with cure of fungal infections like ringworm, jock itch, or athlete’s foot.[5] However, that study was limited by a lack of control group.

    Does bitter orange help with weight loss?

    What are bitter orange’s main drawbacks?

    Bitter orange supplements, typically standardized to synephrine content, seem to have cardiovascular stimulant effects resulting in increased blood pressure and heart rate.[3] There have been reports of adverse reactions in at least 35 people (most commonly palpitations, fainting and dizziness) after taking a synephrine-containing supplement. The specific supplement was not recorded in all cases, but for those cases where it was, the majority of the adverse events occurred with supplements in which synephrine was combined with other active ingredients, including caffeine, deterenol (a synthetic stimulant), theophylline (a bronchodilator), beta-phenylethylamine, and yohimbine. A supplement containing synephrine with caffeine was reported in most cases of cardiovascular adverse events.[6]. Examples of these events included heart rhythm issues,[7] stroke,[8] chest pain,[9] and heart attack.[10]

    Topical bitter orange products may cause irritation and increased sensitivity to the sun, increasing the risk for sunburns.[11]

    Bitter orange might cause drug interactions. Some studies show that bitter orange juice increases blood levels of medications broken down by the liver enzyme called cytochrome P450 (CYP) 3A4. This seems to be due to the furanocoumarin constituents contained in certain citrus fruits.[12] Theoretically, bitter orange supplements that contain furanocoumarins can affect medications that need to be processed by the CYP3A4 enzyme in the liver.

    Does bitter orange increase blood pressure?

    How does bitter orange work?

    The synephrine in bitter oranges is thought to work as a sympathetic adrenergic agonist, stimulating receptors involved in the “fight or flight” response. These effects stimulate the cardiovascular system resulting in increased heart rate and blood pressure. Also, these effects may stimulate metabolism, resting metabolic rate and lipolysis (breakdown of fat). Appetite may also be suppressed via slowed movement of food through the gastrointestinal tract.[2] [6]

    What are other names for Bitter orange

    Note that Bitter orange is also known as:
    • Bitter Orange
    • P-synephrine
    • Citrus Aurantium
    • Synephrine
    Bitter orange should not be confused with:

    Dosage information

    A recommended dosage is 10-20mg, taken thrice a day.

    Acute dosages of 50mg are also frequently used, although not thrice a day.

    Frequently asked questions

    What is bitter orange?

    Bitter orange, also known as Citrus aurantium, is a citrus fruit originally used in Traditional Chinese medicine for stomach ailments, such as constipation, diarrhea, and indigestion.[1] Today, bitter orange extract, standardized to p-synephrine content, commonly occurs in multi-ingredient formulations labeled as ephedra-free supplements for weight loss: p-synephrine is an alkaloid compound structurally similar to adrenaline and the banned dietary supplement ephedrine.[2] The pharmacologic and pharmacokinetic properties of p-synephrine vary from its structural analogues enough to mitigate the risks previously seen with ephedrine-containing supplements. [1]. p-synephrine should also not be confused with m-synephrine, a synthetic amine derivative of synephrine. m-synephrine does not meet the FDA dietary supplement definition and is a prohibited ingredient.

    Is bitter orange considered a performance-enhancing supplement for athletes?

    The National Collegiate Athletic Association (NCAA) lists synephrine (bitter orange) as a banned stimulant. One small study found that taking 100 mg of synephrine slightly enhanced muscle endurance during resistance exercise compared to control.[13]

    A longer-duration study found that 4 weeks of daily administration of a supplement containing 20 mg synephrine improved some areas of exercise performance, but after 8 weeks no clear differences compared to the supplement without synephrine were noted.[4]

    What are bitter orange’s main benefits?

    There is interest in using bitter orange for weight loss and improvement in body composition (fat loss). However, this is not supported by clinical data.[3] Bitter orange is also used for athletic performance, but its benefit is not clear.[4]

    One study found that applying bitter orange oil 20–25% to affected skin for 1 to 3 weeks was associated with cure of fungal infections like ringworm, jock itch, or athlete’s foot.[5] However, that study was limited by a lack of control group.

    Does bitter orange help with weight loss?

    Limited research did not find a benefit. An analysis of 3 small studies found that taking 10–54 mg of synephrine daily for 6–8 weeks had no significant effects on weight loss or fat mass.[3]

    Limited research suggests that bitter orange supplements may increase fat oxidation during exercise and affect resting metabolic rate. One small study of 14 healthy adults found that taking a single dose of p-synephrine prior to one hour of cycling exercise, at a dosage of 3 mg of synephrine per kg of body weight (3 mg/kg), increased the amount of fat burned and decreased the amount of carbohydrates utilized, but did not affect total energy expenditure compared to placebo.[14]. Another small study found that 10 individuals given 50 mg of synephrine had a 65 kcal increase in their resting metabolic rate compared to placebo, but this result was not significant.[15]

    What are bitter orange’s main drawbacks?

    Bitter orange supplements, typically standardized to synephrine content, seem to have cardiovascular stimulant effects resulting in increased blood pressure and heart rate.[3] There have been reports of adverse reactions in at least 35 people (most commonly palpitations, fainting and dizziness) after taking a synephrine-containing supplement. The specific supplement was not recorded in all cases, but for those cases where it was, the majority of the adverse events occurred with supplements in which synephrine was combined with other active ingredients, including caffeine, deterenol (a synthetic stimulant), theophylline (a bronchodilator), beta-phenylethylamine, and yohimbine. A supplement containing synephrine with caffeine was reported in most cases of cardiovascular adverse events.[6]. Examples of these events included heart rhythm issues,[7] stroke,[8] chest pain,[9] and heart attack.[10]

    Topical bitter orange products may cause irritation and increased sensitivity to the sun, increasing the risk for sunburns.[11]

    Bitter orange might cause drug interactions. Some studies show that bitter orange juice increases blood levels of medications broken down by the liver enzyme called cytochrome P450 (CYP) 3A4. This seems to be due to the furanocoumarin constituents contained in certain citrus fruits.[12] Theoretically, bitter orange supplements that contain furanocoumarins can affect medications that need to be processed by the CYP3A4 enzyme in the liver.

    Does bitter orange increase blood pressure?

    Some limited research suggests that bitter orange supplements may increase blood pressure, while other research found no effect. A meta-analysis of small randomized controlled studies suggests that taking bitter orange extract alone or with other ingredients for 56–60 days increases systolic blood pressure by up to 6.4 mmHg compared to control; however, there was no significant effect on diastolic blood pressure. Acute administration of bitter orange extract tended to increase blood pressure over 3 hours, but this result was not statistically significant.[3] One randomized crossover trial of 15 healthy, young adults given a single dose of bitter orange supplement containing 108 mg of synephrine, which was included in the above meta-analysis, reported that the participants given synephrine experienced modestly increased blood pressure and heart rate for up to 5 hours compared to placebo.[16] In another small study, in which participants were given a single, smaller dose of 27 mg of synephrine and monitored for 8 hours, no significant difference from placebo was seen on t blood pressure or electrocardiogram (QT interval).[17] In a small study of healthy young adults sitting quietly for 3 hours after taking a single dose of 103 mg p-synephrine, alone or with 240 mg caffeine, blood pressure and heart rate were not affected compared to placebo.[18] These results suggest that caffeine and synephrine may not always have synergistic effects in the short term.

    A small study of 10 healthy adults considered 2 different dietary supplements containing synephrine and compared heart rate and blood pressure results with placebo after a single dose (Advantra Z, containing 46.9 mg synephrine, and Xenadrine EFX, containing 5.5 mg synephrine). Interestingly, the Xenadrine EFX group experienced more blood pressure and heart rate elevations than the Advantra group, possibly due to other ingredients in the supplement.[19]

    The longer-term effects of a 20 mg daily dose of synephrine were examined in an 8 week study of healthy, young, resistance-trained males; researchers found no changes in blood pressure or heart rate compared to control.[4].

    How does bitter orange work?

    The synephrine in bitter oranges is thought to work as a sympathetic adrenergic agonist, stimulating receptors involved in the “fight or flight” response. These effects stimulate the cardiovascular system resulting in increased heart rate and blood pressure. Also, these effects may stimulate metabolism, resting metabolic rate and lipolysis (breakdown of fat). Appetite may also be suppressed via slowed movement of food through the gastrointestinal tract.[2] [6]

    Update History

    References

    1. ^Bitter Orange: National Center for Complementary and Integrative Health(May 2020)
    2. ^Haaz S, Fontaine KR, Cutter G, Limdi N, Perumean-Chaney S, Allison DBCitrus aurantium and synephrine alkaloids in the treatment of overweight and obesity: an update.Obes Rev.(2006-Feb)
    3. ^Koncz D, Tóth B, Bahar MA, Roza O, Csupor DThe Safety and Efficacy of (Bitter Orange) Extracts and -Synephrine: A Systematic Review and Meta-Analysis.Nutrients.(2022-Sep-28)
    4. ^Jung YP, Earnest CP, Koozehchian M, Cho M, Barringer N, Walker D, Rasmussen C, Greenwood M, Murano PS, Kreider RBEffects of ingesting a pre-workout dietary supplement with and without synephrine for 8 weeks on training adaptations in resistance-trained males.J Int Soc Sports Nutr.(2017)
    5. ^Ramadan W, Mourad B, Ibrahim S, Sonbol FOil of bitter orange: new topical antifungal agent.Int J Dermatol.(1996-Jun)
    6. ^de Jonge MLL, Kieviet LC, Sierts M, Egberink LB, van der Heyden MAGReview of Case Reports on Adverse Events Related to Pre-workout Supplements Containing Synephrine.Cardiovasc Toxicol.(2023-Jan)
    7. ^Nasir JM, Durning SJ, Ferguson M, Barold HS, Haigney MCExercise-induced syncope associated with QT prolongation and ephedra-free Xenadrine.Mayo Clin Proc.(2004-Aug)
    8. ^Bouchard NC, Howland MA, Greller HA, Hoffman RS, Nelson LSIschemic stroke associated with use of an ephedra-free dietary supplement containing synephrine.Mayo Clin Proc.(2005-Apr)
    9. ^Gange CA, Madias C, Felix-Getzik EM, Weintraub AR, Estes NAVariant angina associated with bitter orange in a dietary supplement.Mayo Clin Proc.(2006-Apr)
    10. ^Thomas JE, Munir JA, McIntyre PZ, Ferguson MASTEMI in a 24-year-old man after use of a synephrine-containing dietary supplement: a case report and review of the literature.Tex Heart Inst J.(2009)
    11. ^Ulbricht C, Costa D, Giese N, Isaac R, Liu A, Liu Y, Osho O, Poon L, Rusie E, Stock T, Weissner W, Windsor RCAn evidence-based systematic review of bitter orange (Citrus aurantium) by the Natural Standard Research Collaboration.J Diet Suppl.(2013-Dec)
    12. ^Costache II, Miron A, Hăncianu M, Aursulesei V, Costache AD, Aprotosoaie ACPharmacokinetic Interactions between Cardiovascular Medicines and Plant Products.Cardiovasc Ther.(2019)
    13. ^Ratamess NA, Bush JA, Kang J, Kraemer WJ, Stohs SJ, Nocera VG, Leise MD, Diamond KB, Faigenbaum ADThe effects of supplementation with P-Synephrine alone and in combination with caffeine on resistance exercise performance.J Int Soc Sports Nutr.(2015)
    14. ^Gutiérrez-Hellín J, Ruiz-Moreno C, Del Coso JAcute p-synephrine ingestion increases whole-body fat oxidation during 1-h of cycling at Fatmax.Eur J Nutr.(2020-Oct)
    15. ^Stohs SJ, Preuss HG, Keith SC, Keith PL, Miller H, Kaats GREffects of p-synephrine alone and in combination with selected bioflavonoids on resting metabolism, blood pressure, heart rate and self-reported mood changesInt J Med Sci.(2011 Apr 28)
    16. ^Bui LT, Nguyen DT, Ambrose PJBlood pressure and heart rate effects following a single dose of bitter orangeAnn Pharmacother.(2006 Jan)
    17. ^Min B, Cios D, Kluger J, White CMAbsence of QTc-interval-prolonging or hemodynamic effects of a single dose of bitter-orange extract in healthy subjectsPharmacotherapy.(2005 Dec)
    18. ^Ratamess NA, Bush JA, Stohs SJ, Ellis NL, Vought IT, O'Grady EA, Kuper JD, Hasan SB, Kang J, Faigenbaum ADAcute cardiovascular effects of bitter orange extract (p-synephrine) consumed alone and in combination with caffeine in human subjects: A placebo-controlled, double-blind study.Phytother Res.(2018-Jan)
    19. ^Haller CA, Benowitz NL, Jacob PHemodynamic effects of ephedra-free weight-loss supplements in humans.Am J Med.(2005-Sep)