View source for Synephrine

{{Distinguish|m-synephrine|meta-synephrine}}

{{Drugbox
| Verifiedfields = changed
| verifiedrevid = 470475376
| IUPAC_name = 4-[1-hydroxy-2-(methylamino)ethyl]phenol
| image = Synephrine.svg

<!--Clinical data-->
| tradename = 
| pregnancy_category = 
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| routes_of_administration =  

<!--Pharmacokinetic data-->
| bioavailability =  
| protein_bound =  
| metabolism =  
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<!--Identifiers-->
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 94-07-5
| ATC_prefix = C01
| ATC_suffix = CA08
| ATC_supplemental =  {{ATC|S01|GA06}}
| PubChem = 7172
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| ChemSpiderID = 6904
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| UNII = PEG5DP7434
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07148
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 29081
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 33720

<!--Chemical data-->
| chemical_formula =  
| C=9 | H=13 | N=1 | O=2 
| molecular_weight = 167.205 g/mol
| smiles = OC(c1ccc(O)cc1)CNC
| InChI = 1/C9H13NO2/c1-10-6-9(12)7-2-4-8(11)5-3-7/h2-5,9-12H,6H2,1H3
| InChIKey = YRCWQPVGYLYSOX-UHFFFAOYAW
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
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'''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.<ref name="pmid15497209">{{cite journal |pmid=15497209 |year=2004 |last1=Jordan |first1=S |last2=Murty |first2=M |last3=Pilon |first3=K |title=Products containing bitter orange or synephrine: Suspected cardiovascular adverse reactions |volume=171 |issue=8 |pages=993–4 |journal=CMAJ}}</ref> Among other commonly consumed citrus fruits, clementine mandarins have high levels of synephrine.<ref>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 [http://www.ncbi.nlm.nih.gov/pubmed/21147342 PMID 21147342]</ref> Dietary supplements generally supply single oral doses of 3–30&nbsp;mg, while as a pharmaceutical agent it is given orally or by [[parenteral]] injection in 20–100&nbsp;mg doses as a [[vasoconstrictor]] to [[hypotensive]] patients.<ref>{{cite book |last1=Baselt |first1=Randall C. |title=Disposition of Toxic Drugs and Chemicals in Man |edition=8th |publisher=Biomedical Publications |location=Foster City, California |year=2008 |pages=1471–2 |isbn=978-0-9626523-7-0}}</ref>

==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%.<ref>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.</ref> These investigations in man were consistent with the results of earlier experiments in animals carried out by the same research group.<ref>M. L. Tainter and M. A. Seidenfeld (1930). "Comparative actions of sympathomimetic compounds: synephrine-isomers and -ketone." ''J. Pharmacol. Exp. Ther.'' '''40''' 23-42.</ref>

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 [[structural isomerism|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 isomer|para]] position, whereas in neosynephrine it is at the [[meta-|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).<ref>{{cite journal |doi=10.4065/81.12.1630 |title=Ischemic Colitis Associated with Use of a Bitter Orange-Containing Dietary Weight-Loss Supplement |year=2006 |last1=Sultan |first1=Shahnaz |last2=Spector |first2=Jeremy |last3=Mitchell |first3=Robert M. |journal=Mayo Clinic Proceedings |volume=81 |issue=12 |pages=1630–1 |pmid=17165643}}</ref>

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 [[Central nervous system|CNS]].{{Citation needed|date=April 2011}}

Synephrine can also cause [[arrhythmia]]s.<ref name=liv><nowiki>http://www.slv.se/templates/SLV_Page.aspx?id=11592&epslanguage=SV</nowiki>{{dead link|date=August 2012}} Livsmedelsverket (Swedish FDA){{full|date=November 2012}}</ref> It has some similarity to [[ephedrine]] <ref name=liv/> and can produce similar symptoms under certain circumstances (see [[Ephedrine#Adverse effects|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".<ref>{{cite journal |pmid=20069086 |year=2009 |last1=Thomas |first1=JE |last2=Munir |first2=JA |last3=McIntyre |first3=PZ |last4=Ferguson |first4=MA |title=STEMI in a 24-year-old man after use of a synephrine-containing dietary supplement: A case report and review of the literature |volume=36 |issue=6 |pages=586–90 |pmc=2801940 |journal=Texas Heart Institute journal}}</ref>

==Natural Occurrence==
A survey of the distribution of synephrine amongst the higher plants was published in 1970 by Wheaton and Stewart.<ref>T. A. Wheaton and I. Stewart (1970). "The distribution of tyramine, N-methyltyramine, hordnine, octopamine and synephrine in higher plants. ''Lloydia'' '''33''' 244-254.</ref>

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''.<ref>{{cite book |last1=Shulgin |first1=Alexander |last2=Shulgin |first2=Ann |year=1997 |page=671 |title=Tihkal: The Continuation |location=Berkeley |publisher=Transform Press |isbn=0-9630096-9-9}}</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, 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.

==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.<ref>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.</ref><ref>
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.</ref>


Some comparisons with [[octopamine]] have been performed.<ref name="pmid2833972">{{cite journal |doi=10.1111/j.1476-5381.1988.tb11449.x |title=Activities of octopamine and synephrine stereoisomers on α-adrenoceptors |year=1988 |last1=Brown |first1=C.M. |last2=McGrath |first2=J.C. |last3=Midgley |first3=J.M. |last4=Muir |first4=A.G.B. |last5=O'Brien |first5=J.W. |last6=Thonoor |first6=C.M. |last7=Williams |first7=C.M. |last8=Wilson |first8=V.G. |journal=British Journal of Pharmacology |volume=93 |issue=2 |pages=417–29 |pmid=2833972 |pmc=1853804}}</ref> There is some evidence that it may act at [[Beta-3 adrenergic receptor|β<sub>3</sub> adrenergic receptors]].<ref name="pmid10344530">{{cite journal |doi=10.1007/PL00005357 |title=Selective activation of β3-adrenoceptors by octopamine: Comparative studies in mammalian fat cells |year=1999 |last1=Carpéné |first1=C. |last2=Galitzky |first2=Jean |last3=Fontana |first3=E. |last4=Atgié |first4=Claude |last5=Lafontan |first5=Max |last6=Berlan |first6=Michel |journal=Naunyn-Schmiedeberg's Archives of Pharmacology |volume=359 |issue=4 |pmid=10344530 |pages=310–21}}</ref>

Synephrine has been shown to be an [[agonist]] of the [[trace amine-associated receptor 1|TAAR1]].<ref name="pmid15860375">{{cite journal |doi=10.1016/j.tips.2005.03.007 |title=A renaissance in trace amines inspired by a novel GPCR family |year=2005 |last1=Lindemann |first1=Lothar |last2=Hoener |first2=Marius C. |journal=Trends in Pharmacological Sciences |volume=26 |issue=5 |pages=274–81 |pmid=15860375}}</ref>

==Toxicity==
An acute toxicity study of several phenethylamines, including synephrine (referred to as "Sympatol"), carried out by Lands and Grant showed that the LD<sub>50</sub> of synephrine, administered i.v. in mice, was 270 mg/kg.<ref>A. M. Lands and J. I. Grant (1952). "The vasopressor action and toxicity of cyclohexylethylamine derivatives." ''J. Pharmacol. Exp. Ther.'' '''106''' 341-345.</ref>

==See also==
* [[Octopamine]]
* [[Halostachine]]
* [[Tyramine]]
* [[N-Methyltyramine]]

==References==
{{reflist}}

==External links==
* <nowiki>http://www.mayoclinicproceedings.com/content/80/4/541.refs</nowiki>{{dead link|date=August 2012}} Ischemic Stroke Associated With Use of an Ephedra-Free Dietary Supplement Containing Synephrine (Mayo Clinic)
*{{cite news |first1=Mary |last1=Duenwald |date=January 6, 2004 |title=Slim Pickings: Looking Beyond Ephedra |url=http://www.nytimes.com/2004/01/06/health/slim-pickings-looking-beyond-ephedra.html |work=The New York Times |accessdate=August 1, 2012}}
* [http://www.itmonline.org/arts/syneph.htm SYNEPHRINE: Is Chih-shih (Zhishi) Toxic?]

{{Neurotransmitters}}
{{Cardiac stimulants excluding cardiac glycosides}}
{{Adrenergics}}
{{TAAR ligands}}
{{Phenethylamines}}

[[Category:Phenethylamines]]
[[Category:Alpha-adrenergic agonists]]
[[Category:Proarrhythmic agents]]
[[Category:Phenols]]
[[Category:Alcohols]]

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