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Unripe, dried fruits from Asian cultivars of [[Citrus aurantium]] (known in Traditional Chinese Medicine as "Zhi shi") contain synephrine (to about 0.2%). Extracts thereof are today the main source of naturally occurring synephrine.<ref>{{cite journal |doi=10.1016/S0021-9673(97)00779-6 |title=High-performance liquid chromatography–electrospray mass spectrometry in phytochemical analysis of sour orange (''Citrus aurantium'' L.) |year=1997 |last1=He |first1=Xian-guo |last2=Lian |first2=Li-zhi |last3=Lin |first3=Long-ze |last4=Bernart |first4=Matthew W |journal=Journal of Chromatography A |volume=791 |pages=127–134}}</ref>
Unripe, dried fruits from Asian cultivars of [[Citrus aurantium]] (known in Traditional Chinese Medicine as "Zhi shi") contain synephrine (to about 0.2%). Extracts thereof are today the main source of naturally occurring synephrine.<ref>{{cite journal |doi=10.1016/S0021-9673(97)00779-6 |title=High-performance liquid chromatography–electrospray mass spectrometry in phytochemical analysis of sour orange (''Citrus aurantium'' L.) |year=1997 |last1=He |first1=Xian-guo |last2=Lian |first2=Li-zhi |last3=Lin |first3=Long-ze |last4=Bernart |first4=Matthew W |journal=Journal of Chromatography A |volume=791 |pages=127–134}}</ref>


Synephrine and related [[alkaloids]] are also found in [[citrus]] fruit juices, particularly in [[bitter orange]] products and certain [[mandarin orange]] cultivars. Concentrations ranged from 55 to 160&nbsp;mg/L in juice products obtained from the Satsuma mandarin variety.<ref>{{cite journal |doi=10.1021/jf801225n |title=Synephrine Content of Juice from Satsuma Mandarins (Citrus unshiu Marcovitch) |year=2008 |last1=Dragull |first1=Klaus |last2=Breksa Iii |first2=Andrew P. |last3=Cain |first3=Brian |journal=Journal of Agricultural and Food Chemistry |volume=56 |issue=19 |pages=8874–8 |pmid=18771270}}</ref>
Synephrine and related [[alkaloids]] are also found in [[citrus]] fruit juices, particularly in [[bitter orange]] products and certain [[mandarin orange]] cultivars, as well as in "sweet" oranges. Concentrations ranged from 55 to 160&nbsp;mg/L in juice products obtained from the Satsuma mandarin variety grown in California.<ref>{{cite journal |doi=10.1021/jf801225n |title=Synephrine Content of Juice from Satsuma Mandarins (Citrus unshiu Marcovitch) |year=2008 |last1=Dragull |first1=Klaus |last2=Breksa Iii |first2=Andrew P. |last3=Cain |first3=Brian |journal=Journal of Agricultural and Food Chemistry |volume=56 |issue=19 |pages=8874–8 |pmid=18771270}}</ref> Sweet oranges of the Tarocco, Naveline and Navel varieties, bought on the Italian market, were found to contain ~ 13-34 μg/g (corresponding to 13-34 mg/kg) synephrine (with roughly equal concentrations in juice and separated pulp), while commercial Italian orange juices contained ~ 13-32 mg/L of synephrine. From these results, it was calculated that eating one "average" Tarocco orange would provide ~ 6 mg of synephrine.<ref>L. Mattoli, F. Cangi, A. Maidecchi, C. Ghiara, M. Tubaro, and P. Traldi (2005). "A rapid liquid chromatography electrospray ionization mass spectrometry method for evaluation of synephrine in ''Citrus aurantium'' L. samples." ''J. Agric. Fd. Chem.'' '''53''' 9860–9866.</ref> Juices from "sweet" oranges purchased in Brazilian markets were found to contain ~ 10-22 mg/L synephrine; commercial orange soft drinks had an average synephrine content of ~ 1 mg/L.<ref>S. M. Vieira, K. H. Theodoro, M. B. A. Glória (2007). "Profile and levels of bioactive amines in orange juice and orange soft drink." ''Food Chem.'' '''100''' 895-903.</ref>


Synephrine occurs in [[Citrus aurantium|marmalade orange]] products.
Synephrine occurs in [[Citrus aurantium|marmalade orange]] products.


Revision as of 19:59, 30 January 2013

Not to be confused with m-synephrine or meta-synephrine.
Synephrine
Clinical data
ATC code
Identifiers
  • 4-[1-hydroxy-2-(methylamino)ethyl]phenol
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.002.092 Edit this at Wikidata
Chemical and physical data
FormulaC9H13NO2
Molar mass167.205 g/mol g·mol−1
3D model (JSmol)
  • OC(c1ccc(O)cc1)CNC
  • InChI=1S/C9H13NO2/c1-10-6-9(12)7-2-4-8(11)5-3-7/h2-5,9-12H,6H2,1H3 checkY
  • Key:YRCWQPVGYLYSOX-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Synephrine (also called Sympatol and oxedrine) is an alkaloid, a naturally-occurring plant constituent, and is commonly used as a drug for causing weight loss. While its effectiveness is widely debated, synephrine has gained significant popularity as an alternative to ephedrine, a related substance which has been made illegal or restricted in many countries due to health risks and its use as a precursor in the illicit manufacturing of methamphetamine. There is however no diversion of synephrine for the manufacture of amphetamines, since the presence of the phenolic group and absence of an α-methyl group in its molecular structure makes it unsuitable for such purposes. Synephrine is derived primarily from the immature fruit of Citrus aurantium, a relatively small citrus tree, commonly called Bitter Orange, Sour Orange, and "Zhi shi" (in Chinese Traditional medicine). Products containing bitter orange or synephrine are suspected of causing adverse cardiovascular reactions.[1] Among other commonly consumed citrus fruits, clementine mandarins have high levels of synephrine.[2] Dietary supplements generally supply single oral doses of 3–30 mg, while as a pharmaceutical agent it is given orally or by parenteral injection in 20–100 mg doses as a vasoconstrictor to hypotensive patients.[3]

Older Clinical Studies

Synephrine was studied for its therapeutic potential in man as a pressor, vasoconstrictor, and for other properties by Tainter and colleagues in the early 1930s. These researchers observed that racemic synephrine caused a rise in blood pressure of 25-30 mm of Hg, lasting 30-60 minutes, when given in intramuscular doses of 200+ mg, or intravenous doses of 50+ mg. No changes in blood pressure were produced by subcutaneous doses up to 200 mg. Oral doses of 500 - 1500 mg had no effect on blood pressure or respiration, but the highest dose did cause nausea/vomiting and increased the pulse rate by 12%.[4] These investigations in man were consistent with the results of earlier experiments in animals carried out by the same research group.[5]

More recent pharmacological studies of synephrine are referred to in the Pharmacology section below.

Synephrine and neosynephrine

There has been some confusion surrounding synephrine and phenylephrine (also known as "Neosynephrine" and "Meta-synephrine"), one of its positional isomers, because of the similarity in common names. The chemicals are similar in structure; the only difference is the location of the aromatic hydroxyl group. In synephrine, the hydroxyl is at the para position, whereas in neosynephrine it is at the meta position. Each compound has differing biological properties, however.

Associated risks

Many diet products such as "Stacker 2", "Xenadrine-EFX", etc. contain a "stack" of synephrine along with caffeine, sometimes with an NSAID. The Mayo Clinic published a report that suggested a link between Stacker 2 pills and increased risk of ischemic stroke, increased blood pressure, and myocardial infarction (heart attack).[6]

Due to the aromatic hydroxyl group, the pharmacological profile is different to ephedrine; synephrine as a catecholamine analog is acting predominantly on peripheral adrenergic receptors and does not have a pronounced effect on the CNS.[citation needed]

Synephrine can also cause arrhythmias.[7] It has some similarity to ephedrine [7] and can produce similar symptoms under certain circumstances (see ephedrine adverse effects).

Following the presentation of a healthy young man with a myocardial infarction, a case study and subsequent literature review found that the makers of "nutritional supplements" who replaced ephedrine with its analogs p-synephrine and/or p-octopamine from "bitter orange" had in effect simply found a loophole in the FDA's April 2004 regulation banning ephedra in those supplements by substituting a similar substance the regulation did not address, while permitting them to label the products as "ephedra-free".[8]

Natural Occurrence

A survey of the distribution of synephrine amongst the higher plants was published in 1970 by Wheaton and Stewart.[9]

Synephrine is reported as naturally occurring in the following cactus species: Coryphantha cornifera, C. durangensis, C. elephantides, C. greenwoodii, C. ottonis, C. pectinata, C. poselgeriana, C. ramillosa, C. runyonii, Dolichothele sphaerica, D. surculosa, and D. uberiformis.[10]

Unripe, dried fruits from Asian cultivars of Citrus aurantium (known in Traditional Chinese Medicine as "Zhi shi") contain synephrine (to about 0.2%). Extracts thereof are today the main source of naturally occurring synephrine.[11]

Synephrine and related alkaloids are also found in citrus fruit juices, particularly in bitter orange products and certain mandarin orange cultivars, as well as in "sweet" oranges. Concentrations ranged from 55 to 160 mg/L in juice products obtained from the Satsuma mandarin variety grown in California.[12] Sweet oranges of the Tarocco, Naveline and Navel varieties, bought on the Italian market, were found to contain ~ 13-34 μg/g (corresponding to 13-34 mg/kg) synephrine (with roughly equal concentrations in juice and separated pulp), while commercial Italian orange juices contained ~ 13-32 mg/L of synephrine. From these results, it was calculated that eating one "average" Tarocco orange would provide ~ 6 mg of synephrine.[13] Juices from "sweet" oranges purchased in Brazilian markets were found to contain ~ 10-22 mg/L synephrine; commercial orange soft drinks had an average synephrine content of ~ 1 mg/L.[14]


Synephrine occurs in marmalade orange products.

Pharmacology

Two comprehensive reviews of the pharmacology of synephrine, including discussions of safety issues related to human use as "dietary supplements", have recently been published.[15][16]


Some comparisons with octopamine have been performed.[17] There is some evidence that it may act at β3 adrenergic receptors.[18]

Synephrine has been shown to be an agonist of the TAAR1.[19]

Toxicity

An acute toxicity study of several phenethylamines, including synephrine (referred to as "Sympatol"), carried out by Lands and Grant showed that the LD50 of synephrine, administered i.v. in mice, was 270 mg/kg.[20]

See also

References

  1. ^ Jordan, S; Murty, M; Pilon, K (2004). "Products containing bitter orange or synephrine: Suspected cardiovascular adverse reactions". CMAJ. 171 (8): 993–4. PMID 15497209.
  2. ^ Uckoo RM, , G K. Jayaprakasha, Nelson SD, Patil BS (2011), Rapid simultaneous determination of amines and organic acids in citrus using high-performance liquid chromatography. Talanta, 83: 948–954 PMID 21147342
  3. ^ Baselt, Randall C. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, California: Biomedical Publications. pp. 1471–2. ISBN 978-0-9626523-7-0.
  4. ^ A. B. Stockton, P. T. Pace and M. L. Tainter (1931). "Some clinical actions and therapeutic uses of racemic synephrine." J. Pharmacol. Exp. Ther. 41 11-20.
  5. ^ M. L. Tainter and M. A. Seidenfeld (1930). "Comparative actions of sympathomimetic compounds: synephrine-isomers and -ketone." J. Pharmacol. Exp. Ther. 40 23-42.
  6. ^ Sultan, Shahnaz; Spector, Jeremy; Mitchell, Robert M. (2006). "Ischemic Colitis Associated with Use of a Bitter Orange-Containing Dietary Weight-Loss Supplement". Mayo Clinic Proceedings. 81 (12): 1630–1. doi:10.4065/81.12.1630. PMID 17165643.
  7. ^ a b http://www.slv.se/templates/SLV_Page.aspx?id=11592&epslanguage=SV[dead link‍] Livsmedelsverket (Swedish FDA)[full citation needed]
  8. ^ Thomas, JE; Munir, JA; McIntyre, PZ; Ferguson, MA (2009). "STEMI in a 24-year-old man after use of a synephrine-containing dietary supplement: A case report and review of the literature". Texas Heart Institute journal. 36 (6): 586–90. PMC 2801940. PMID 20069086.
  9. ^ T. A. Wheaton and I. Stewart (1970). "The distribution of tyramine, N-methyltyramine, hordnine, octopamine and synephrine in higher plants. Lloydia 33 244-254.
  10. ^ Shulgin, Alexander; Shulgin, Ann (1997). Tihkal: The Continuation. Berkeley: Transform Press. p. 671. ISBN 0-9630096-9-9.
  11. ^ He, Xian-guo; Lian, Li-zhi; Lin, Long-ze; Bernart, Matthew W (1997). "High-performance liquid chromatography–electrospray mass spectrometry in phytochemical analysis of sour orange (Citrus aurantium L.)". Journal of Chromatography A. 791: 127–134. doi:10.1016/S0021-9673(97)00779-6.
  12. ^ Dragull, Klaus; Breksa Iii, Andrew P.; Cain, Brian (2008). "Synephrine Content of Juice from Satsuma Mandarins (Citrus unshiu Marcovitch)". Journal of Agricultural and Food Chemistry. 56 (19): 8874–8. doi:10.1021/jf801225n. PMID 18771270.
  13. ^ L. Mattoli, F. Cangi, A. Maidecchi, C. Ghiara, M. Tubaro, and P. Traldi (2005). "A rapid liquid chromatography electrospray ionization mass spectrometry method for evaluation of synephrine in Citrus aurantium L. samples." J. Agric. Fd. Chem. 53 9860–9866.
  14. ^ S. M. Vieira, K. H. Theodoro, M. B. A. Glória (2007). "Profile and levels of bioactive amines in orange juice and orange soft drink." Food Chem. 100 895-903.
  15. ^ S. J. Stohs, H. G. Preuss and M. Shara (2011). "The Safety of Citrus aurantium (Bitter Orange) and its primary protoalkaloid p-synephrine." Phytother. Res. 25 1421-1428.
  16. ^ L. G. Rossato, V. M. Costa, R. P. Limberger, M. de Lourdes Bastos, and F. Remião (2011). "Synephrine: from trace concentrations to massive consumption in weight-loss." Food Chem. Toxicol. 49 8-16.
  17. ^ Brown, C.M.; McGrath, J.C.; Midgley, J.M.; Muir, A.G.B.; O'Brien, J.W.; Thonoor, C.M.; Williams, C.M.; Wilson, V.G. (1988). "Activities of octopamine and synephrine stereoisomers on α-adrenoceptors". British Journal of Pharmacology. 93 (2): 417–29. doi:10.1111/j.1476-5381.1988.tb11449.x. PMC 1853804. PMID 2833972.
  18. ^ Carpéné, C.; Galitzky, Jean; Fontana, E.; Atgié, Claude; Lafontan, Max; Berlan, Michel (1999). "Selective activation of β3-adrenoceptors by octopamine: Comparative studies in mammalian fat cells". Naunyn-Schmiedeberg's Archives of Pharmacology. 359 (4): 310–21. doi:10.1007/PL00005357. PMID 10344530.
  19. ^ Lindemann, Lothar; Hoener, Marius C. (2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends in Pharmacological Sciences. 26 (5): 274–81. doi:10.1016/j.tips.2005.03.007. PMID 15860375.
  20. ^ A. M. Lands and J. I. Grant (1952). "The vasopressor action and toxicity of cyclohexylethylamine derivatives." J. Pharmacol. Exp. Ther. 106 341-345.
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