Bitter orange

Last Updated: September 28 2022

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.

Bitter orange is most often used for.



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1.

Sources and Structure

1.1

Sources

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.[1][2] The bitter orange (sometimes also called Seville or Sour orange[3]) is not a common fruit consumed except perhaps in Iran due to its bitter and sour taste;[3] the common orange is citrus sinensis.

It can be found in:

  • Citrus aurantium fruit (8848.8mg/kg dry weight; 96% total protoalkaloids[4])
  • Standard Citrus aurantium extract (71.5g/kg or 7.1% dry weight; 92.2% total protoalkaloids[4]), although methanolic extracts may be more balanced between octopamine and synephrine (0.253 and 0.142%, respectively[5])

1.2

Structure

The term synephrine tends to exclusively refer to parasynephrine or p-synephrine (insofar that the two are mostly synonymous in common usage[1]) although two other variants, specifically metasynephrine (m-synephrine) and orthosynephrine (o-synephrine); they are thought to have similar properties,[6] although p-synephrine is the particular variant found in the traditional medicine citrus aurantium (alongside the molecule it is made from, octopamine[7][2]).

2.

Pharmacology

2.1

Metabolism

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[8] and it has been detected in human urine independent of supplementation or oral ingestion.[9][10]

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[11] (similar to its parent molecule octopamine,[12] and the lack of difference in the metabolism of monoamines and their N-methylated derivatives has been noted previously with noradrenaline and normetanephrine[13]).

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

2.2

Elimination

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;[14] 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.

Neurology

3.1

Headache 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[15]) and synephrine, as well as other trace amines (tyramine, octopamine) can be detected in plasma[16] at levels much higher in persons with cluster headaches[17] and in migraines with aurae.[18] 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).[18]

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

4.

Cardiovascular Health

4.1

Blood 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.[19] 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.[20] A 27 mg dose does not appear to affect blood pressure over eight hours.[21]

5.

Obesity and Fat Mass

5.1

Metabolic 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 [22] and this was without any influence on blood pressure or cognition.[22]

5.2

Mechanisms

P-synephrine is a beta-agonist compound similar to ephedrine[23][24]. It can increase the metabolic rate via increasing lipolysis and basal metabolic rate.[1] 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.[25] In both the cases of alpha and beta agonism, the effects of both forms of synephrine are much less than that of noradrenaline.

5.3

Human studies

It has been implicated in increasing the thermic effect of food, but one study noted this effect only in women.[26]

6.

Nutrient-Nutrient Interactions

6.1

Citrus 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;[22] 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.[22]

6.2

Caffeine

Like ephedrine, P-synephrine also shows synergism with caffeine and is more pronounced in naive caffeine users.[27]

7.

Safety profile

7.1

General

P-synephrine does not seem to be a causative agent in increasing blood pressure[28][29][26]

The Bitter Orange itself (the parent plant) has been linked to increased systolic and diastolic blood pressure.[30] 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).[28]

Overall, usage of P-synephrine appears to be quite safe and free of most adverse side effects.[31]

7.2

Drug 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.[32]

References
1.^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 updateObes Rev.(2006 Feb)
3.^Marchei E, Pichini S, Pacifici R, Pellegrini M, Zuccaro PA rapid and simple procedure for the determination of synephrine in dietary supplements by gas chromatography-mass spectrometryJ Pharm Biomed Anal.(2006 Jun 16)
4.^Nelson BC, Putzbach K, Sharpless KE, Sander LCMass spectrometric determination of the predominant adrenergic protoalkaloids in bitter orange (Citrus aurantium)J Agric Food Chem.(2007 Nov 28)
9.^KAKIMOTO Y, ARMSTRONG MDThe phenolic amines of human urineJ Biol Chem.(1962 Jan)
10.^PISANO JJ, OATES JA Jr, KARMEN A, SJOERDSMA A, UDENFRIEND SIdentification of p-hydroxy-alpha-(methylaminomethyl) benzyl alcohol (synephrine) in human urineJ Biol Chem.(1961 Mar)
11.^Suzuki O, Matsumoto T, Oya M, Katsumata YOxidation of synephrine by type A and type B monoamine oxidaseExperientia.(1979 Oct 15)
14.^Thevis M1, Koch A, Sigmund G, Thomas A, Schänzer WAnalysis of octopamine in human doping control samplesBiomed Chromatogr.(2012 May)
17.^D'Andrea G, Terrazzino S, Leon A, Fortin D, Perini F, Granella F, Bussone GElevated levels of circulating trace amines in primary headachesNeurology.(2004 May 25)
18.^D'Andrea G, Granella F, Leone M, Perini F, Farruggio A, Bussone GAbnormal platelet trace amine profiles in migraine with and without auraCephalalgia.(2006 Aug)
20.^Bui LT, Nguyen DT, Ambrose PJBlood pressure and heart rate effects following a single dose of bitter orangeAnn Pharmacother.(2006 Jan)
23.^Jordan R, Midgley JM, Thonoor CM, Williams CMBeta-adrenergic activities of octopamine and synephrine stereoisomers on guinea-pig atria and tracheaJ Pharm Pharmacol.(1987 Sep)
25.^Brown CM, McGrath JC, Midgley JM, Muir AG, O'Brien JW, Thonoor CM, Williams CM, Wilson VGActivities of octopamine and synephrine stereoisomers on alpha-adrenoceptorsBr J Pharmacol.(1988 Feb)
27.^Seifert JG, Nelson A, Devonish J, Burke ER, Stohs SJEffect of acute administration of an herbal preparation on blood pressure and heart rate in humansInt J Med Sci.(2011 Mar 2)
28.^Haller CA, Benowitz NL, Jacob P 3rdHemodynamic effects of ephedra-free weight-loss supplements in humansAm J Med.(2005 Sep)
30.^Bui LT, Nguyen DT, Ambrose PJBlood pressure and heart rate effects following a single dose of bitter orangeAnn Pharmacother.(2006 Jan)
32.^Nguyen DT, Bui LT, Ambrose PJResponse of CEDIA amphetamines assay after a single dose of bitter orangeTher Drug Monit.(2006 Apr)
34.^Bloomer RJ, Fisher-Wellman KH, Hammond KG, Schilling BK, Weber AA, Cole BJDietary supplement increases plasma norepinephrine, lipolysis, and metabolic rate in resistance trained menJ Int Soc Sports Nutr.(2009 Jan 28)
35.^McCarthy CG, Farney TM, Canale RE, Alleman RJ Jr, Bloomer RJA finished dietary supplement stimulates lipolysis and metabolic rate in young men and womenNutr Metab Insights.(2011 Dec 6)
36.^Haller CA, Duan M, Jacob P 3rd, Benowitz NHuman pharmacology of a performance-enhancing dietary supplement under resting and exercise conditionsBr J Clin Pharmacol.(2008 Jun)