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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.

Our evidence-based analysis on synephrine features 34 unique references to scientific papers.

Research analysis led by and reviewed by the Examine team.
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Research Breakdown on Synephrine

1Sources and Structure


P-Synephrine (P-hydroxy-α-{methylaminomethyl}benzylalcohol) is a protoalkaloid compound and trace amine that can be endogenously produced in the human body, or can be found in high levels in the bitter orange (citrus aurantium) traditional chinese medicine and supplement.[7][8] The bitter orange (sometimes also called Seville or Sour orange[9]) is not a common fruit consumed except perhaps in Iran due to its bitter and sour taste;[9] the common orange is citrus sinensis.

It can be found in:

  • Citrus aurantium fruit (8848.8mg/kg dry weight; 96% total protoalkaloids[10])

  • Standard Citrus aurantium extract (71.5g/kg or 7.1% dry weight; 92.2% total protoalkaloids[10]), although methanolic extracts may be more balanced between octopamine and synephrine (0.253 and 0.142%, respectively[11])


The term synephrine tends to exclusively refer to parasynephrine or p-synephrine (insofar that the two are mostly synonymous in common usage[7]) although two other variants, specifically metasynephrine (m-synephrine) and orthosynephrine (o-synephrine); they are thought to have similar properties,[12] although p-synephrine is the particular variant found in the traditional medicine citrus aurantium (alongside the molecule it is made from, octopamine[13][8]).



Synephrine is known to be an endogenous metabolite of octopamine metabolism, specifically its N-methylated derivative; its synthesis has been detected in the rat brain[14] and it has been detected in human urine independent of supplementation or oral ingestion.[15][16]

Synephrine appears to be an endogenously produced end product of tyramine metabolism, as tyramine is metabolized into octopamine (another trace amino acid) which is then oxidized into synephrine

Synephrine is a substrate for the monoamine oxidase (MAO) enzymes (Km of 250µM and a Vmax of 32.6nM/mg protein/30 minutes), seeming to be metabolized more by MAO-A than MAO-B[17] (similar to its parent molecule octopamine,[18] and the lack of difference in the metabolism of monoamines and their N-methylated derivatives has been noted previously with noradrenaline and normetanephrine[19]).

The oxidation of octopamine into synephrine, as well as the oxidation of synephrine itself, is conducted via the MAO enzymes and mostly by MAO-A


Oral supplementation of synephrine up to 150mg, at no time point, increases urinary octopamine above the LOQ when assessed after the 24 hours following a single dose;[20] this is relevant as octopamine is banned by WADA whereas synephrine is not, and octopamine itself can be detected following oral ingestion of octopamine supplements.


3.1Headache and Migraine

Synephrine is known to be endogenously produced as a metabolite in tyramine metabolism as it can be decarboxylated in plants from tyramine to produce synephrine (to give off carbon dioxide[21]) and synephrine, as well as other trace amines (tyramine, octopamine) can be detected in plasma[22] at levels much higher in persons with cluster headaches[23] and in migraines with aurae.[24] Synephrine specifically is also higher in persons with migraines with aurea (0.72+/-0.44ng/108 platelets) although not in migraines without aurae (0.37+/-0.29ng/108 platelets) which were similar to normal controls (0.33+/-0.25ng/108 platelets).[24]

Trace amine metabolism (tyramine based) appears to be perturbed in the pathology of migraines, and due to this platelet concentrations of synephrine may be higher than in persons without migraines or those with migraines but no aurae associated with the migraine. Significance to oral supplementation not known

4Cardiovascular Health

4.1Blood Pressure

A single dose of 50 mg p-synephrine, when taken by healthy subjects in a rested state over the course of 75 minutes, does not appear to significantly influence blood pressure nor heart rate.[25] However, participants consumed the synephrine with a V-8 juice drink. A single dose of 50 mg synephrine taken alone and compared to lactose placebo has been shown to significantly increase blood pressure by 7 mmHg (systolic) and 2.6 mmHg (diastolic) over five hours.[26] A 27 mg dose does not appear to affect blood pressure over eight hours.[27]

5Obesity and Fat Mass

5.1Metabolic Rate

A single dose of 50mg p-synephrine, when measured over the next 75 minutes in otherwise healthy subjects in a rested state, has been noted to increase by 65kcal [25] and this was without any influence on blood pressure or cognition.[25]


P-synephrine is a beta-agonist compound similar to ephedrine[28][29]. It can increase the metabolic rate via increasing lipolysis and basal metabolic rate.[7] These effects are independent of diet for the most part, and can exert a passive increase in basal metabolic rate to produce weight loss over an extended period of time.

Synephrine also has alpha-adrenergic antagonist capabilities. Affecting both the A1 and A2 receptors, albeit with a different potency.[30] In both the cases of alpha and beta agonism, the effects of both forms of synephrine are much less than that of noradrenaline.

5.3Human studies

It has been implicated in increasing the thermic effect of food, but one study noted this effect only in women.[31]

6Nutrient-Nutrient Interactions

6.1Citrus Flavonoids (Naringenin and Hesperidin)

50mg p-synephrine can increase metabolic rate by 65kcal relative to placebo (which noted a 30kcal decrease; measurements taken in the fasted state over 75 minutes), and the addition of 600mg naringenin increases this increase in metabolic rate to 129kcal and a further increase of 100mg hesperidin to both the aforementioned ingredients can again increase the metabolic rate to 183kcal;[25] consuming a higher total level of hesperidin (1,000mg) with the aforementioned doses of p-synephrine and naringenin resulted in a lesser increase of the metabolic rate by 79kcal relative to control.[25]


Like ephedrine, P-synephrine also shows synergism with caffeine and is more pronounced in naive caffeine users.[4]

7Safety profile


P-synephrine does not seem to be a causative agent in increasing blood pressure[32][5][31]

The Bitter Orange itself (the parent plant) has been linked to increased systolic and diastolic blood pressure.[26] While a common patented blend of P-synephrine known as Xenadrine EFX (containing just 5.5 mg synephrine) has been linked to an increase in blood pressure, another patented blend, Advantra-Z (which contains a significantly higher dose of synephrine at 46.9 mg along with active bioflavonoids such as naringen and hesperidin) has not. Both appear to increase heart rate from baseline though (16.7 BPM and 11.7 BPM, respectively).[32]

Overall, usage of P-synephrine appears to be quite safe and free of most adverse side effects.[33]

7.2Drug Testing

P-synephrine has failed to cause a false positive for drug testing (via a CEDIA amphetamines assay) following ingestion of 54mg p-synephrine via 900mg citrus aurantium extract.[34]


  1. ^ Bloomer RJ, et al. Effect of the dietary supplement Meltdown on catecholamine secretion, markers of lipolysis, and metabolic rate in men and women: a randomized, placebo controlled, cross-over study. Lipids Health Dis. (2009)
  2. ^ Bloomer RJ, et al. Dietary supplement increases plasma norepinephrine, lipolysis, and metabolic rate in resistance trained men. J Int Soc Sports Nutr. (2009)
  3. ^ McCarthy CG, et al. A finished dietary supplement stimulates lipolysis and metabolic rate in young men and women. Nutr Metab Insights. (2011)
  4. ^ a b Seifert JG, et al. Effect of acute administration of an herbal preparation on blood pressure and heart rate in humans. Int J Med Sci. (2011)
  5. ^ a b Sale C, et al. Metabolic and physiological effects of ingesting extracts of bitter orange, green tea and guarana at rest and during treadmill walking in overweight males. Int J Obes (Lond). (2006)
  6. ^ Haller CA, et al. Human pharmacology of a performance-enhancing dietary supplement under resting and exercise conditions. Br J Clin Pharmacol. (2008)
  7. ^ a b c Haaz S, et al. Citrus aurantium and synephrine alkaloids in the treatment of overweight and obesity: an update. Obes Rev. (2006)
  8. ^ a b Determination of adrenergic agonists from extracts and herbal products of Citrus aurantium L. var. amara by LC.
  9. ^ a b Marchei E, et al. A rapid and simple procedure for the determination of synephrine in dietary supplements by gas chromatography-mass spectrometry. J Pharm Biomed Anal. (2006)
  10. ^ a b Nelson BC, et al. Mass spectrometric determination of the predominant adrenergic protoalkaloids in bitter orange (Citrus aurantium). J Agric Food Chem. (2007)
  11. ^ Shawky E. Determination of Synephrine and Octopamine in Bitter Orange Peel by HPTLC with Densitometry. J Chromatogr Sci. (2013)
  12. ^ National Toxicology Program. NTP Toxicology and Carcinogenesis Studies of Phenylephrine Hydrochloride (CAS No. 61-76-7) in F344/N Rats and B6C3F1 Mice (Feed Studies). Natl Toxicol Program Tech Rep Ser. (1987)
  13. ^ Ibrahim KE, et al. Quantitative measurement of octopamines and synephrines in urine using capillary column gas chromatography negative ion chemical ionization mass spectrometry. Anal Chem. (1984)
  14. ^ Boulton AA, Wu PH. Biosynthesis of cerebral phenolic amines. I. In vivo formation of p-tyramine, octopamine, and synephrine. Can J Biochem. (1972)
  15. ^ KAKIMOTO Y, ARMSTRONG MD. The phenolic amines of human urine. J Biol Chem. (1962)
  16. ^ PISANO JJ, et al. Identification of p-hydroxy-alpha-(methylaminomethyl) benzyl alcohol (synephrine) in human urine. J Biol Chem. (1961)
  17. ^ Suzuki O, et al. Oxidation of synephrine by type A and type B monoamine oxidase. Experientia. (1979)
  18. ^ Suzuki O, et al. Oxidation of phenylethanolamine and octopamine by type A and type B monoamine oxidase. Effect of substrate concentration. Biochem Pharmacol. (1979)
  19. ^ Houslay MD, Tipton KF. A kinetic evaluation of monoamine oxidase activity in rat liver mitochondrial outer membranes. Biochem J. (1974)
  20. ^ Thevis M1, et al. Analysis of octopamine in human doping control samples. Biomed Chromatogr. (2012)
  21. ^ Bartley GE, Breksa AP 3rd, Ishida BK. PCR amplification and cloning of tyrosine decarboxylase involved in synephrine biosynthesis in Citrus. N Biotechnol. (2010)
  22. ^ D'Andrea G, et al. HPLC electrochemical detection of trace amines in human plasma and platelets and expression of mRNA transcripts of trace amine receptors in circulating leukocytes. Neurosci Lett. (2003)
  23. ^ D'Andrea G, et al. Elevated levels of circulating trace amines in primary headaches. Neurology. (2004)
  24. ^ a b D'Andrea G, et al. Abnormal platelet trace amine profiles in migraine with and without aura. Cephalalgia. (2006)
  25. ^ a b c d e Stohs SJ, et al. Effects of p-synephrine alone and in combination with selected bioflavonoids on resting metabolism, blood pressure, heart rate and self-reported mood changes. Int J Med Sci. (2011)
  26. ^ a b Bui LT, Nguyen DT, Ambrose PJ. Blood pressure and heart rate effects following a single dose of bitter orange. Ann Pharmacother. (2006)
  27. ^ Min B, et al. Absence of QTc-interval-prolonging or hemodynamic effects of a single dose of bitter-orange extract in healthy subjects. Pharmacotherapy. (2005)
  28. ^ Jordan R, et al. Beta-adrenergic activities of octopamine and synephrine stereoisomers on guinea-pig atria and trachea. J Pharm Pharmacol. (1987)
  29. ^ Arch JR. beta(3)-Adrenoceptor agonists: potential, pitfalls and progress. Eur J Pharmacol. (2002)
  30. ^ Brown CM, et al. Activities of octopamine and synephrine stereoisomers on alpha-adrenoceptors. Br J Pharmacol. (1988)
  31. ^ a b Increase in the Thermic Effect of Food in Women by Adrenergic Amines Extracted from Citrus Aurantium.
  32. ^ a b Haller CA, Benowitz NL, Jacob P 3rd. Hemodynamic effects of ephedra-free weight-loss supplements in humans. Am J Med. (2005)
  33. ^ Stohs SJ, Preuss HG, Shara M. The safety of Citrus aurantium (bitter orange) and its primary protoalkaloid p-synephrine. Phytother Res. (2011)
  34. ^ Nguyen DT, Bui LT, Ambrose PJ. Response of CEDIA amphetamines assay after a single dose of bitter orange. Ther Drug Monit. (2006)