View source for Synephrine

{{Hatnote|This article will focus, insofar as possible, on synephrine itself, rather than on the drug mixtures containing it.}}
{{chembox
| ImageFile =Synephrine.svg
| ImageSize = 
| ImageFile1=Synephrine Ball and Stick.png
| PIN =4-[1-Hydroxy-2-(methylamino)ethyl]phenol
| OtherNames =''p''-Synephrine; Oxedrine; 4,β-Dihydroxy-''N''-methylphenethylamine

| Section1 = {{Chembox Identifiers
| Abbreviations =
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = PEG5DP7434
| 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
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 33720
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C9H13NO2/c1-10-6-9(12)7-2-4-8(11)5-3-7/h2-5,9-12H,6H2,1H3
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = YRCWQPVGYLYSOX-UHFFFAOYSA-N
| CASNo =94-07-5
| CASNo_Ref = {{cascite|correct|CAS}}
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 6904
| PubChem = 7172
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = 
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 29081
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07148
| SMILES = CNCC(O)c1ccc(O)cc1
| MeSHName =
 }}

| Section2 = {{Chembox Properties
| Formula = C<sub>9</sub>H<sub>13</sub>NO<sub>2</sub>
| MolarMass = 167.21 g/mol
| Appearance = colorless solid 
| Density = 
| MeltingPtC = 162 to 164
| MeltingPt_notes = (R-(−)-enantiomer); 184 to 185 °C (racemate)
| BoilingPt = 
| Solubility = soluble}}

| Section6 = {{Chembox Pharmacology
| ATCCode_prefix = C01
| ATCCode_suffix = CA08
| ATC_Supplemental = {{ATC|S01|GA06}}, {{ATCvet|S01|FB90}}
}}

| Section7 = {{Chembox Hazards
| MainHazards = 
| FlashPt = 
| AutoignitionPt = 
 }}
}}

'''Synephrine''', or, more specifically, '''''p''-synephrine''', is an [[alkaloid]], occurring naturally in some plants and animals, and also in approved drugs products as its ''m''-substituted analog known as neo-synephrine.<ref>{{Cite web|url=https://compendium.ch/mpro/mnr/22158/html/fr?Platform=Desktop|title=Neo-Synephrine HCl - compendium.ch|last=SA|first=HCI Solutions|website=compendium.ch|access-date=2016-03-06|archive-date=2020-07-25|archive-url=https://web.archive.org/web/20200725033715/https://compendium.ch/fr/product/1092556-neo-synephrine-hcl-inj-los-10-mg-ml/mpro|url-status=dead}}</ref> ''p''-Synephrine (or formerly '''Sympatol''' and '''oxedrine''' [<nowiki/>[[British Approved Name|BAN]]]) and ''m''-synephrine are known for their longer acting [[adrenergic]] effects compared to [[epinephrine]] and [[norepinephrine]]. This substance is present at very low concentrations in common foodstuffs such as [[orange juice]] and other orange (''[[Citrus]]'' species) products, both of the "sweet" and "bitter" variety. The preparations used in [[traditional Chinese medicine]] ('''TCM'''), also known as Zhi Shi (枳实), are the immature and dried whole oranges from ''[[Citrus aurantium]]'' (''Fructus Aurantii Immaturus''). Extracts of the same material or purified synephrine are also marketed in the US, sometimes in combination with [[caffeine]], as a weight-loss-promoting [[dietary supplement]] for oral consumption. While the traditional preparations have been in use for millennia as a component of TCM-formulas, synephrine itself is not an approved [[over the counter drug]]. As a pharmaceutical, ''m''-synephrine ([[phenylephrine]]) is still used as a [[sympathomimetic]] (i.e. for its [[hypertensive]] and [[vasoconstrictor]] properties), mostly by injection for the treatment of emergencies such as [[Shock (circulatory)|shock]], and rarely orally for the treatment of bronchial problems associated with [[asthma]] and [[hay-fever]].{{efn|Synephrine does however not appear in the current FDA [[Approved Drug Products with Therapeutic Equivalence Evaluations|"Orange Book"]] or the 2012 ''[[Physicians' Desk Reference]]''.}}

There is a difference between studies concerning synephrine as a single chemical entity (synephrine can exist in the form of either of two [[stereoisomers]], d- and l-synephrine, which are chemically and pharmacologically distinct), and synephrine which is mixed with other drugs and/or botanical extracts in a "supplement", as well as synephrine which is present as only one chemical component in a naturally-occurring mixture of [[phytochemicals]] such as the rind or fruit of a bitter orange. Mixtures containing synephrine as only one of their chemical components (regardless of whether these are of synthetic or natural origin) should not be assumed to produce exactly the same biological effects as synephrine alone.<ref>{{cite journal | author = Wagner H., Ulrich-Merzenich G. | year = 2009 | title = Synergy research: approaching a new generation of phytopharmaceuticals | journal = Phytomedicine | volume = 16 | issue = 2–3| pages = 97–110 | doi = 10.1016/j.phymed.2008.12.018 | pmid = 19211237 | s2cid = 25766699 }}</ref>

In physical appearance, synephrine is a colorless, crystalline solid and is water-soluble. Its molecular structure is based on a [[phenethylamine]] skeleton and is related to those of many other drugs and to the major [[neurotransmitters]] epinephrine and norepinephrine.

== Natural occurrences ==
Synephrine, although already known as a synthetic [[organic compound]], was first isolated as a [[natural product]] from the leaves of various ''[[Citrus]]'' trees, and its presence noted in different ''Citrus'' juices, by Stewart and co-workers in the early 1960s.<ref name = Stew>{{cite journal | author = Stewart I., Newhall W. F., Edwards G. J. | year = 1964 | title = The isolation and identification of synephrine in the leaves and fruit of Citrus |journal=J. Biol. Chem. | volume = 239 | issue = 3 | pages = 930–932 | doi = 10.1016/S0021-9258(18)51679-3 | doi-access = free }}</ref><ref name="Stew2">[http://www.fshs.org/Proceedings/Password%20Protected/1963%20Vol.%2076/242-245%20%28STEWART%29.pdf] {{dead link|date=December 2013}}</ref> A survey of the distribution of synephrine amongst the higher plants was published in 1970 by Wheaton and Stewart.<ref>{{cite journal | author = Wheaton T. A., Stewart I. | year = 1970 | title = The distribution of tyramine, N-methyltyramine, hordenine, octopamine and synephrine in higher plants | journal = Lloydia | volume = 33 | issue = 2| pages = 244–254 | pmid = 5495514 }}</ref> It has subsequently been detected in ''[[Evodia]]''<ref>{{cite journal | author = Ko H. C., Chen K. T., Chen C. F., Su J. P., Chen C. M., Wang G. J. | year = 2006 | title = Chemical and biological comparisons on ''Evodia'' with two related species of different locations and conditions | journal = Journal of Ethnopharmacology | volume = 108 | issue = 2| pages = 257–263 | doi = 10.1016/j.jep.2006.05.020 | pmid = 16824714 }}</ref> and ''[[Zanthoxylum]]'' species,<ref>{{cite journal | author = Swinehart J. A., Stermitz F. R. | year = 1980 | title = Bishordeninyl terpene alkaloids and other constituents of ''Zanthoxylum culantrillo'' and ''Z. coriaceum'' | journal = Phytochemistry | volume = 19 | issue = 6| pages = 1219–1223 | doi = 10.1016/0031-9422(80)83087-1 | bibcode = 1980PChem..19.1219S }}</ref> all plants of the family Rutaceae.

Trace levels (0.003%) of synephrine have also been detected in the dried leaves of ''[[Pogostemon cablin]]'' ([[patchouli]], Lamiaceae).<ref>{{cite journal | author = Kim S. P., Moon E., Nam S. H., Friedman M. | year = 2012 | title = Composition of Herba Pogostemonis water extract and protection of infected mice against ''Salmonella typhimurium''-induced liver damage and mortality by stimulation of innate immune cells | journal = Journal of Agricultural and Food Chemistry | volume = 60 | issue = 49| pages = 12122–12130 | doi = 10.1021/jf304466t | pmid = 23186318 }}</ref> It is also found in certain cactus species of the genera ''[[Coryphantha]]'' and ''[[Dolichothele]]''.<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>

However, this compound is found predominantly in a number of ''Citrus'' species, including "bitter" orange varieties.

=== In ''Citrus'' ===
Extracts of unripe fruit from Asian cultivars of ''[[Citrus aurantium]]'' (commonly known as "bitter" orange), collected in China, were reported to contain synephrine levels of about 0.1–0.3%, or ~1–3&nbsp;mg/g;<ref>{{cite journal | author = Kusu F., Li X.-D., Takamura K. | year = 1992 | title = Determination of synephrine and N-methyltyramine in Zhishi and Zhike (immature Citrus fruits) by high-performance liquid chromatography with electrochemical detection | journal = Chemical & Pharmaceutical Bulletin | volume = 40 | issue = 12| pages = 3284–3286 | doi = 10.1248/cpb.40.3284 | doi-access = free }}</ref> Analysis of dried fruit of ''C. aurantium'' grown in Italy showed a concentration of synephrine of ~1&nbsp;mg/g, with peel containing over three times more than the pulp.<ref name = Pellat>{{cite journal | author = Pellati F., Benvenuti S., Melegari M. | year = 2005 | title = Enantioselective LC analysis of synephrine in natural products on a protein-based chiral stationary phase | journal = Journal of Pharmaceutical and Biomedical Analysis | volume = 37 | issue = 5| pages = 839–849 | doi = 10.1016/j.jpba.2004.09.008 | pmid = 15862657 }}</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&nbsp;mg/kg) synephrine (with roughly equal concentrations in juice and separated pulp); from these results, it was calculated that eating one "average" Tarocco orange would result in the consumption of ~6&nbsp;mg of synephrine.<ref name = Mat>{{cite journal | author = Mattoli L., Cangi F., Maidecchi A., Ghiara C., Tubaro M., Traldi P. | year = 2005 | title = A rapid liquid chromatography electrospray ionization mass spectrometry method for evaluation of synephrine in ''Citrus aurantium'' L. samples | journal = Journal of Agricultural and Food Chemistry | volume = 53 | issue = 26| pages = 9860–9866 | doi = 10.1021/jf051270+ | pmid = 16366666 }}</ref>

An analysis of 32 different orange "jams", originating mostly in the US and UK, but including samples from France, Italy, Spain, or Lebanon, showed synephrine levels ranging from 0.05&nbsp;mg/g–0.0009&nbsp;mg/g{{efn|About 1.0–0.02 mg/serving, based on a serving size of ~20g.}} in those jams made from bitter oranges, and levels of 0.05&nbsp;mg/g–0.006&nbsp;mg/g{{efn|About 1.0–0.1 mg/serving.}} of synephrine in jams made from sweet oranges.<ref name = Av>{{cite journal | author = Avula B., Upparapalli S. K., Khan I. A. | year = 2007 | title = Simultaneous analysis of adrenergic amines and flavonoids in citrus peel jams and fruit juices by liquid chromatography: part 2 | journal = Journal of AOAC International | volume = 90 | issue = 3| pages = 633–40 | doi = 10.1093/jaoac/90.3.633 | pmid = 17580614 | doi-access = free }}</ref>

Synephrine has been found in [[marmalade]] made from ''[[Citrus unshiu]]'' (Satsuma mandarin)<ref name = XRef>{{cite web|url=http://www.plantnames.unimelb.edu.au/Sorting/Citrus.html |title=Cross-reference for ''Citrus'' species and common names |publisher=Plantnames.unimelb.edu.au |access-date=2013-12-10}}</ref> obtained in Japan, at a concentration of ~0.12&nbsp;mg/g (or about 2.4&nbsp;mg/20g serving).<ref name = Kusu>{{cite journal | author = Kusu F., Matsumoto K., Arai K., Takamura K. | year = 1996 | title = Determination of synephrine enantiomers in food and conjugated synephrine in urine by high-performance liquid chromatography with electrochemical detection | journal = Analytical Biochemistry | volume = 235 | issue = 2| pages = 191–194 | doi = 10.1006/abio.1996.0111 | pmid = 8833327 }}</ref> Most of the orange marmalades made in the US are produced using "sweet" oranges (''[[Citrus sinensis|C. sinensis]]''), whereas "bitter" or Seville oranges (''C. aurantium'') are used for making the more traditional, bitterer marmalades in the United Kingdom.<ref name = Blum>{{cite web|url=http://abc.herbalgram.org/site/DocServer/Bitter_Orange_Peel_and_Synephrine.pdf|title=American Botanical Council : Bitter Orange Peel and Synephrine|website=Abc.herbalgram.org|access-date=27 January 2022}}</ref>

A sample of commercial Japanese ''C. unshiu'' juice was found to contain ~0.36&nbsp;mg/g synephrine (or roughly 360&nbsp;mg/L),<ref name = Kusu/> while in juice products obtained from a Satsuma mandarin variety grown in California, levels of synephrine ranged from 55 to 160&nbsp;mg/L .<ref>{{cite journal | author = Dragull K., Breksa A. P., Cain B. | year = 2008 | title = Synephrine content of juice from Satsuma Mandarins (''Citrus unshiu'' Marcovitch.) | journal = Journal of Agricultural and Food Chemistry | volume = 56 | issue = 19| pages = 8874–8878 | doi = 10.1021/jf801225n | pmid = 18771270 }}</ref>

Juices from "sweet" oranges purchased in Brazilian markets were found to contain ~10–22&nbsp;mg/L synephrine; commercial orange soft drinks obtained on the Brazilian market had an average synephrine content of ~1&nbsp;mg/L.<ref>{{cite journal | author = Vieira S. M., Theodoro K. H., Glória M. B. A. | year = 2007 | title = Profile and levels of bioactive amines in orange juice and orange soft drink | journal = Food Chemistry | volume = 100 | issue = 3| pages = 895–903 | doi = 10.1016/j.foodchem.2005.10.050 }}</ref> Commercial Italian orange juices contained ~13–32&nbsp;mg/L of synephrine<ref name = Mat/>

In a survey of over 50 citrus fruit juices, either commercially-prepared or hand-squeezed from fresh fruit, obtained on the US market, Avula and co-workers found synephrine levels ranging from ~4–60&nbsp;mg/L;{{efn|Corresponding to roughly 1–15 mg/serving, assuming a 1-cup or 250 mL serving size.}} no synephrine was detected in juices from grapefruit, lime, or lemon.<ref name = Av/>
 
An analysis of the synephrine levels in a range of different citrus fruits, carried out on juices that had been extracted from fresh, peeled fruit, was reported by Uckoo and co-workers, with the following results:
Marrs sweet orange (''C. sinensis'' Tan.): ~85&nbsp;mg/L; Nova tangerine (''[[Citrus reticulata|C. reticulata]]'' Tan.): ~78&nbsp;mg/L; clementine (''C. clementina'' Tan.): ~115&nbsp;mg/L; Meyer lemon (''C. limon'' Tan.) ~3&nbsp;mg/kg; Ugli tangelo (''C. reticulata'' × ''C. paradisi'') ~47&nbsp;mg/kg. No synephrine was detected in: Rio Red grapefruit (''C. paradisi'' Macf.); Red-fleshed pummelo (''C. grandis'' Tan.); or Wekiwa tangelo (''C. reticulata'' × ''C. paradisi'').<ref name = XRef/><ref>{{cite journal | author = Uckoo R. M., Jayaprakasha G. K., Nelson S. D., Patil B. S. | year = 2011 | title = Rapid simultaneous determination of amines and organic acids in citrus using high-performance liquid chromatography | journal = Talanta | volume = 83 | issue = 3| pages = 948–54 | doi = 10.1016/j.talanta.2010.10.063 | pmid = 21147342 }}</ref>

Numerous additional comparable analyses of the synephrine content of ''Citrus'' fruits and products derived from them may be found in the research literature.

=== In humans and other animals ===
Low levels of synephrine have been found in normal human urine,<ref name = Ib>{{cite journal | author = Ibrahim K. E., Couch M. W., Williams C. M., Budd M. B., Yost R. A., Midgley J. M. | year = 1984 | title = Quantitative measurement of octopamines and synephrines in urine using capillary column gas chromatography negative ion chemical ionization mass spectrometry | journal = Analytical Chemistry | volume = 56 | issue = 9| pages = 1695–1699 | doi = 10.1021/ac00273a037 | pmid = 6435479 }}</ref><ref>{{cite journal | author = Wang R., Wan L., Li Q., Liu X., Huang Y. | year = 2007 | title = Chemiluminescence of synephrine based on the cerium(IV)–rhodamine B system | journal = Luminescence | volume = 22 | issue = 2| pages = 140–146 | doi = 10.1002/bio.937 | pmid = 17089346 }}</ref> as well as in other mammalian tissue.<ref>{{cite journal | author = Watson D.G., Midgley J.M., Chen R.N., Huang W., Bain G.M., McDonald N.M., Reid J.L., McGhee C.N.J. | year = 1990 | title = Analysis of biogenic amines and their metabolites in biological tissues and fluids by gas chromatography—negative ion chemical ionization mass spectrometry (GC-NICIMS) | journal = Journal of Pharmaceutical and Biomedical Analysis | volume = 8 | issue = 8–12| pages = 899–904 | doi = 10.1016/0731-7085(90)80139-g | pmid = 2100639 }}</ref><ref>{{cite journal | author = Ibrahim K. E., Couch M. W., Williams C. M., Fregly M. J., Midgley J. M. | year = 1985 | title = ''m''-Octopamine: normal occurrence with ''p''-octopamine in mammalian sympathetic nerves | journal = Journal of Neurochemistry | volume = 44 | issue = 6| pages = 1862–1867 | doi = 10.1111/j.1471-4159.1985.tb07180.x | pmid = 3921667 | s2cid = 7376144 }}</ref> To reduce the likelihood that the synephrine detected in urine had a dietary origin, the subjects tested by Ibrahim and co-workers abstained from the consumption of any citrus products for 48 hours prior to providing urine samples.<ref name = Ib/>

A 2006 study of synephrine in human [[blood platelets]] by D'Andrea and co-workers showed increased levels in platelets from patients suffering from aura-associated migraine (0.72&nbsp;ng/10<sup>8</sup> platelets, compared to 0.33&nbsp;ng/10<sup>8</sup> platelets in control subjects).<ref>{{cite journal | author = D'Andrea G., Granella F., Leone M., Perini F., Farruggio A., Bussone G. | year = 2006 | title = Abnormal platelet trace amine profiles in migraine with and without aura | journal = Cephalalgia | volume = 26 | issue = 8| pages = 968–972 | doi = 10.1111/j.1468-2982.2006.01141.x | pmid = 16886933 | s2cid = 43823090 | doi-access = free }}</ref> Earlier, the same research group had reported a normal human [[blood plasma]] level of synephrine of 0.90–13.69&nbsp;ng/mL.<ref name = Andrea>{{cite journal | author = D'Andrea G., Terrazzino S., Fortina D., Farruggioa A., Rinaldi L., Leon A. | year = 2003 | title = HPLC electrochemical detection of trace amines in human plasma and platelets and expression of mRNA transcripts of trace amine receptors in circulating leukocytes | journal = Neuroscience Letters | volume = 346 | issue = 1–2| pages = 89–92 | doi = 10.1016/s0304-3940(03)00573-1 | pmid = 12850555 | s2cid = 1673803 }}</ref>

=== Stereoisomers ===
Since synephrine exists as either of two [[enantiomers]] (see Chemistry section below for further discussion), which do not produce identical biological effects (see Pharmacology section below) some researchers have examined the [[stereoisomer]]ic composition of synephrine extracted from natural sources. Although it seems clear that synephrine is found in those ''Citrus'' species which have been studied predominantly as the l-isomer,<ref name = Kusu/><ref name = Pel>{{cite journal | author = Pellati F., Benvenuti S., Melegari M., Firenzuoli F. | year = 2002 | title = Determination of adrenergic agonists from extracts and herbal products of ''Citrus aurantium'' L. var. amara by LC. | journal = Journal of Pharmaceutical and Biomedical Analysis | volume = 29 | issue = 6| pages = 1113–1119 | doi = 10.1016/s0731-7085(02)00153-x | pmid = 12110397 }}</ref> low levels of d-synephrine have been detected in juice and marmalade made from ''C. unshiu'',<ref name = Kusu/> and low levels (0.002%) have been reported in fresh fruit from ''C. aurantium''.<ref name = Pel/> There are indications that some d-synephrine may be formed by the [[racemization]] of l-synephrine as a result of the processing of fresh fruit, although this matter has not been completely clarified.<ref>{{cite journal | author = Pellati F., Cannazza G., Benvenuti S. | year = 2010 | title = Study on the racemization of synephrine by off-column chiral high-performance liquid chromatography | journal = Journal of Chromatography A | volume = 1217 | issue = 21| pages = 3503–3510 | doi = 10.1016/j.chroma.2010.03.026 | pmid = 20399443 }}</ref><ref>{{cite journal | author = Kusu F., Matsumoto K., Takamura K. | year = 1995 | title = Direct separation and determination of synephrine enantiomers by high-performance liquid chromatography with electrochemical detection | journal = Chemical & Pharmaceutical Bulletin | url = https://www.jstage.jst.go.jp/article/cpb1958/43/7/43_7_1158/_pdf | volume = 43 | issue = 7| pages = 1158–1161 | doi = 10.1248/cpb.43.1158 | doi-access = free }}</ref> However, regardless of the situation in ''Citrus'' species, Ranieri and McLaughlin reported the ''isolation'' of [[racemic]] (i.e. a mixture of equal amounts of d- and l- stereoisomers) synephrine from a cactus of the genus ''Dolichothele'', under conditions that would be unlikely to cause a significant amount of racemization.<ref>{{cite journal | author = Ranieri R. L., McLaughlin J. L. | year = 1976 | title = Cactus alkaloids. XXVIII. β-Phenethylamine and tetrahydroisoquinoline alkaloids from the Mexican cactus ''Dolichothele longimamma'' | journal = The Journal of Organic Chemistry | volume = 41 | issue = 2| pages = 319–323 | doi = 10.1021/jo00864a030 }}</ref>

===Biosynthesis===
The biosynthesis of synephrine in ''Citrus'' species is believed to follow the pathway: [[tyrosine]] → [[tyramine]] → [[N-methyltyramine|''N''-methyltyramine]] → synephrine, involving the enzymes [[tyrosine decarboxylase]] in the first step, [[Tyramine N-methyltransferase|tyramine ''N''-methyltransferase]] in the second, and ''N''-methyl-tyramine-β-hydroxylase in the third.<ref name = Wheat>{{cite journal | author = Wheaton T. A., Stewart I. | year = 1969 | title = Biosynthesis of synephrine in citrus | journal = Phytochemistry | volume = 8 | issue = 1 | pages = 85–92 | doi = 10.1016/s0031-9422(00)85799-4 | bibcode = 1969PChem...8...85W }}</ref><ref>{{cite journal | author = Bartley A. P. Breksa III, Ishida B. K. | year = 2010 | title = PCR amplification and cloning of tyrosine decarboxylase involved in synephrine biosynthesis in Citrus | journal = New Biotechnology | volume = 27 | issue = 4| pages = 308–316 | doi = 10.1016/j.nbt.2010.04.003 | pmid = 20403465 }}</ref> This pathway differs from that thought to occur in animals, involving [[octopamine]]: tyramine → octopamine → synephrine, where the conversion of tyramine to octopamine is mediated by [[dopamine-β-hydroxylase]], and the conversion of octopamine to synephrine by [[Phenylethanolamine N-methyltransferase|phenylethanolamine ''N''-methyltransferase]].<ref name = Andrea/><ref name = Wheat/>{{Phenylalanine biosynthesis
| caption = In humans, catecholamines and phenethylaminergic trace amines are produced from the amino acid phenylalanine. Abbreviations:
DBH: Dopamine β-hydroxylase; AADC: Aromatic <small>L</small>-amino acid decarboxylase; AAAH: (Biopterin-dependent) aromatic amino acid hydroxylase; COMT: Catechol ''O''-methyltransferase; PNMT: Phenylethanolamine ''N''-methyltransferase
| align =center}}<!--
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==Presence in nutritional/dietary supplements==
Some dietary supplements, sold for the purposes of promoting weight-loss or providing energy, contain synephrine as one of several constituents. Usually, the synephrine is present as a natural component of ''Citrus aurantium'' ("bitter orange"), bound up in the plant matrix, but could also be of synthetic origin, or a purified phytochemical (i.e. extracted from a plant source and purified to chemical homogeneity).<ref name = Blum/><ref name = Sant>{{cite journal | author = Santana J., Sharpless K. E., Nelson B. C. | year = 2008 | title = Determination of para-synephrine and meta-synephrine positional isomers in bitter orange-containing dietary supplements by LC/UV and LC/MS/MS. | journal = Food Chemistry | volume = 109 | issue = 3| pages = 675–682 | doi = 10.1016/j.foodchem.2007.12.076 }}</ref><ref>{{cite journal | pmid = 16164886 | year = 2005 | last1 = Haller | first1 = C. A. | last2 = Benowitz | first2 = N. L. | last3 = Jacob p | first3 = 3rd | title = Hemodynamic effects of ephedra-free weight-loss supplements in humans | journal = The American Journal of Medicine | volume = 118 | issue = 9 | pages = 998–1003 | doi = 10.1016/j.amjmed.2005.02.034 }}</ref> The concentration range found by Santana and co-workers in five different supplements purchased in the US was about 5–14&nbsp;mg/g.<ref name = Sant/>

==Pharmaceutical use==
As a synthetic drug, synephrine first appeared in Europe in the late 1920s, under the name of ''Sympatol''. One of the earliest papers describing its pharmacological and toxicological properties was written by Lasch, who obtained it from the Viennese company Syngala.<ref name = Las>{{cite journal | author = Lasch F | year = 1927 | title = Über die Pharmakologie des Sympathols, einer neuen adrenalinähnlichen Substanz. (Zugleich ein Beitrag zur Frage der chemischen Konstitution und pharmakodynamischen Wirkung) | journal = Naunyn-Schmiedebergs Archiv für Experimentelle Pathologie und Pharmakologie | volume = 124 | issue = 3–4| pages = 231–244 | doi = 10.1007/bf01861902 | s2cid = 24160900 }}</ref> By 1930, ''Sympatol'' was referred to as a Boehringer product,<ref>{{cite journal | author = Hochrein M., Keller J. | year = 1930 | title = Über die Wirkung des Adrenalins und adrenalinverwandter Körper (Sympatol und Ephetonin) auf den Kreislauf | journal = Naunyn-Schmiedebergs Archiv für Experimentelle Pathologie und Pharmakologie | volume = 156 | pages = 37–63 | doi = 10.1007/bf01859312 | s2cid = 28747772 }}</ref> while one of the first US Patents describing its preparation and use was assigned to Frederick Stearns & Co. in 1933.<ref>H. Legerlotz, US Patent 1,932,347 (October 24, 1933).</ref> Despite the date of this patent, clinical and pharmacological research on synephrine obtained from Frederick Stearns & Co was being carried out in the US by 1930.<ref name = Stock>{{cite journal | author = Stockton A. B., Pace P. T., Tainter M. L. | year = 1931 | title = Some clinical actions and therapeutic uses of racemic synephrine | journal = Journal of Pharmacology and Experimental Therapeutics | volume = 41 | pages = 11–20 }}</ref><ref name = Tain>{{cite journal | author = Tainter M. L., Seidenfeld M. A. | year = 1930 | title = Comparative actions of sympathomimetic compounds: synephrine-isomers and -ketone | journal = J. Pharmacol. Exp. Ther. | volume = 40 | pages = 23–42 }}</ref> Writing in 1931, Hartung reported that in 1930 the Council on Pharmacy and Chemistry of the American Medical Association had accepted synephrine for inclusion in its list of “New and Non-Official Remedies” as an agent for the treatment, by either oral or parenteral administration, "of attacks of hay fever, asthma, coughing, spasms of asthma and pertussis (whooping cough)."<ref>{{Cite journal |doi = 10.1001/jama.1930.02710440042013|title = Council on Pharmacy and Chemistry|journal = The Journal of the American Medical Association|year = 1930|volume = 94|issue = 18|page = 1404}}</ref><ref name = Hart>{{cite journal | author = Hartung W | year = 1931 | title = Epinephrine and related compounds: influence of structure on physiological activity | journal = Chemical Reviews | volume = 9 | issue = 3| pages = 389–468 | doi = 10.1021/cr60034a002 }}</ref> However, synephrine was dropped from the council's list in 1934, and its apparent re-advertising as a new drug by the Stearns company ten years later elicited a scathing comment from the Editors of the Journal of the American Medical Association.<ref>{{cite journal | author = Editorial  | year = 1944 | title = Sympatol-Stearns - A triumph of medical misinformation for physicians | journal = Journal of the American Medical Association | volume = 124 | issue = 14| page = 988 | doi = 10.1001/jama.1944.02850140034013 }}</ref> The third edition (1965) of ''Drill's Pharmacology in Medicine'' stated, with reservations, that synephrine was "advertised as an antihistaminic to be used in the treatment of the common cold...", under the trade name of "Synephrin Tartrate", and indicated that the dose was 100&nbsp;mg, given intramuscularly, or subcutaneously.<ref>J. R. DiPalma (Ed.) (1965),''Drill's Pharmacology in Medicine,3rd Ed.'', p.494, McGraw-Hill, New York.</ref> Published in 1966, the ''Textbook of Organic Medicinal and Pharmaceutical Chemistry'' described synephrine (in the form of its racemic tartrate) as a sympathomimetic agent that was "less effective than epinephrine", and which had been used  for the treatment of chronic [[hypotension]], collapse due to shock, and other conditions leading to [[hypotension]].<ref name = Wil>C. O. Wilson, O. Gisvold, and R. F. Doerge (Eds.) (1966). ''Textbook of Organic Medicinal and Pharmaceutical Chemistry, 5th ed.,'' p.438, Lippincott, Philadelphia.</ref> In a later (1972) textbook, synephrine was described as a drug, sold in Europe, that was administered in situations involving shock, such as surgical or [[bacteremic]] shock, and [[spinal anesthesia]]-related shock. The recommended dose was given here as 25–50&nbsp;mg, by intravenous, intramuscular or subcutaneous administration.<ref>D. M. Aviado (Ed.), 1972. ''Krantz & Carr's Pharmacologic Principles of Medical Practice, 8th Ed.'', p.526, Williams & Wilkins, Baltimore.</ref>

There is no mention of synephrine in editions of ''Drill's Pharmacology in Medicine'' later than the 3rd, nor is there any reference to synephrine in the 2012 ''[[Physicians' Desk Reference]]'', nor in the current [[Food and Drug Administration|FDA]] [[Approved Drug Products with Therapeutic Equivalence Evaluations|"Orange Book"]].

One current reference source describes synephrine as a vasoconstrictor that has been given to hypotensive patients, orally or by injection, in doses of 20–100&nbsp;mg.<ref>R. C. Baselt (2008). ''Disposition of Toxic Drugs and Chemicals in Man (8th Ed..)'' pp. 1471–2, Biomedical Publications, Foster City, California. {{ISBN|978-0-9626523-7-0}}.</ref>

One website from a healthcare media company, accessed in February, 2013, refers to oxedrine as being indicated for [[hypotensive]] states, in oral doses of 100–150&nbsp;mg [[List of abbreviations used in medical prescriptions|tid]], and as a "[[conjunctiva]]l decongestant" to be topically applied as a 0.5% solution.<ref>https://www.mims.com/USA/drug/info/oxedrine/?type=full&mtype=generic {{dead link|date=January 2022|fix-attempted=yes}}</ref> However, no supporting references are provided.

==Names==
There has been some confusion about the biological effects of synephrine because of the similarity of this un-prefixed name to the names ''m-synephrine'', ''Meta-synephrine'' and ''Neosynephrine'', all of which refer to a related drug and naturally-occurring [[amine]] more commonly known as [[phenylephrine]]. Although there are chemical and pharmacological similarities between synephrine and phenylephrine, they are nevertheless different substances. The confusion is compounded by the fact that synephrine has been marketed as a drug under numerous different names, including ''Sympatol'', ''Sympathol'', ''Synthenate'', and ''oxedrine'', while phenylephrine has also been called ''m-Sympatol''. The synephrine with which this article deals is sometimes referred to as ''p-synephrine'' in order to distinguish it from its positional isomers, ''m''-synephrine and ''o''-synephrine. A comprehensive listing of alternative names for synephrine may be found in the ChemSpider entry (see Chembox, at right). Confusion exists over the distinctions between ''p''- and ''m''-synephrine.<ref name="G. Rossato, V. M 2011">{{cite journal | author = Rossato L. G., Costa V. M., Limberger R. P., de Lourdes Bastos M., Remião F. | year = 2011 | title =  Synephrine: From trace concentrations to massive consumption in weight-loss| journal =  Food and Chemical Toxicology| volume = 49 | issue = 1| pages = 8–16 |doi=10.1016/j.fct.2010.11.007 | pmid = 21075161 }}</ref> However, an examination of the references cited in support of this statement show that all the evidence for the presence of ''m''-synephrine in ''C. aurantium'' derives from a report by Penzak and co-workers,<ref>{{cite journal | author = Penzak S. R., Jann M. W., Cold J. A., Hon Y. Y., Desai H. D., Gurley B. J. | year = 2001 | title = Seville (sour) orange juice: Synephrine content and cardiovascular effects in normotensive adults | journal = The Journal of Clinical Pharmacology | volume = 41 | issue = 10| pages = 1059–1063 | doi = 10.1177/00912700122012652 | pmid = 11583473 | s2cid = 32631329 }}</ref> whose Abstract states that ''m''-synephrine was found in ''C. aurantium'', whereas a close reading of the text of the paper itself reveals that the authors (although apparently uncertain about which synephrine regio-isomer had been found in the plant by earlier investigators) were aware that their analytical technique could not distinguish between ''m''- and ''p''-synephrine, and did ''not'' claim that ''m''-synephrine was present. Thus the Abstract is at variance with the experimental findings given in the full text of the paper, but this error has propagated through subsequent publications. Even the name "''p''-synephrine" is not unambiguous, since it does not specify stereochemistry. The only completely unambiguous names for synephrine are: (''R'')-(−)-4-[1-hydroxy-2-(methylamino)ethyl]phenol (for the l-enantiomer); (''S'')-(+)-4-[1-hydroxy-2-(methylamino)ethyl]phenol (for the d-enantiomer); and (''R'',''S'')-4-[1-hydroxy-2-(methylamino)ethyl]phenol (for the racemate, or d,l-synephrine) (see [[#Chemistry|Chemistry]] section).

==Chemistry==

===Properties===
In terms of molecular structure, synephrine has a [[phenethylamine]] skeleton, with a [[phenol]]ic [[hydroxyl|hydroxy]]- group, an [[Alcohol (chemistry)|alcohol]]ic hydroxy- group, and an ''N''-methylated [[amino]]-group. Alternatively, synephrine might be described as a [[phenylethanolamine]] with an ''N''-methyl and ''p''-hydroxy substituent. The amino-group confers basic properties on the molecule, whereas the phenolic –OH group is weakly acidic: the apparent (see original article for discussion) pK<sub>a</sub>s for protonated synephrine are 9.55 (phenolic H) and 9.79 (ammonium H).<ref>{{cite journal | author = Kappe T., Armstrong M. D. | year = 1965 | title = Ultraviolet absorption spectra and apparent acidic dissociation constants of some phenolic amines | journal = Journal of Medicinal Chemistry | volume = 8 | issue = 3| pages = 368–374 | doi = 10.1021/jm00327a018 | pmid = 14323148 }}</ref>

Common salts of [[racemic]] synephrine are its [[hydrochloride]], C<sub>9</sub>H<sub>13</sub>NO<sub>2</sub>.HCl, m.p.&nbsp;150–152°,<ref>{{cite journal | author = Bergmann E. D., Sulzbacher M. | year = 1951 | title = A new synthesis of 1-(''m''- and ''p''-hydroxyphenyl)-2-methylaminoethanol (''m''- and ''p''-sympathol) | journal = The Journal of Organic Chemistry | volume = 16 | pages = 84–89 | doi = 10.1021/jo01141a013 }}</ref> the [[oxalate]] (C<sub>9</sub>H<sub>13</sub>NO<sub>2</sub>)<sub>2</sub>.C<sub>2</sub>H<sub>2</sub>O<sub>4</sub>, m.p.&nbsp;221–222&nbsp;°C,<ref name = Stew/> and the [[tartrate]] (Sympatol), (C<sub>9</sub>H<sub>13</sub>NO<sub>2</sub>)<sub>2</sub>.C<sub>4</sub>H<sub>6</sub>O<sub>6</sub>, m.p.&nbsp;188–190&nbsp;°C.<ref name = Wil/><ref>The Merck Index, 10th Ed. (1983), p. 1295, Merck & Co., Rahway, NJ.</ref>

The presence of the hydroxy-group on the [[benzylic]] C of the synephrine molecule creates a [[chiral center]], so the compound exists in the form of two [[enantiomers]], d- and l- synephrine, or as the [[racemic mixture]], d,l- synephrine. The [[dextrorotatory]] d-isomer corresponds to the [[Cahn–Ingold–Prelog priority rules|(''S'')-configuration]], and the [[levorotatory]] l-isomer to the [[Cahn–Ingold–Prelog priority rules|(''R'')-configuration]].<ref name = Midg>J. M. Midgley, C. M. Thonoor, A. F. Drake, C. M. Williams, A. E. Koziol and G. J. Palenik (1989). "The resolution and absolute configuration by X-ray crystallography of the isomeric octopamines and synephrines." ''J. Chem. Soc., Perkin Trans. 2'' 963-969.</ref>

Racemic synephrine has been resolved using ammonium 3-bromo-camphor-8-sulfonate.<ref name = Pellat/><ref name = Midg/> The enantiomers were not characterized as their free bases, but converted to the hydrochloride salts, with the following properties:<ref name = Midg/>

(''S'')-(+)-C<sub>9</sub>H<sub>13</sub>NO<sub>2</sub>.HCl: m.p.&nbsp;178&nbsp;°C; [α] = +42.0°, c 0.1 (H<sub>2</sub>O); (''R'')-(−)-C<sub>9</sub>H<sub>13</sub>NO<sub>2</sub>.HCl: m.p.&nbsp;176&nbsp;°C; [α] = −39.0°, c 0.2 (H<sub>2</sub>O)

(−)-Synephrine, as the free base isolated from a ''Citrus'' source, has m.p.&nbsp;162–164&nbsp;°C (with decomposition).<ref name = Stew/><ref name = Stew2/>{{dead link|date=December 2013}}

The [[X-ray crystallography|X-ray structure]] for synephrine has been determined.<ref name = Midg/>

===Synthesis===
Early and seemingly inefficient syntheses of synephrine were discussed by Priestley and Moness, writing in 1940.<ref>{{cite journal | author = Priestley H. M., Moness E. | year = 1940 | title = A study of the intermediates in the preparation of sympathol | journal = J. Org. Chem. | volume = 40 | issue = 4| pages = 355–361 | doi = 10.1021/jo01210a004 }}</ref> These chemists optimized a route beginning with the ''O''-benzoylation of ''p''-hydroxy-phenacyl chloride, followed by reaction of the resulting ''O''-protected chloride with ''N''-methyl-benzylamine to give an amino-ketone. This intermediate was then hydrolyzed with HCl/alcohol to the ''p''-hydroxy-aminoketone, and the product then reduced catalytically to give (racemic) synephrine.

A later synthesis, due to Bergmann and Sulzbacher, began with the ''O''-benzylation of ''p''-hydroxy-benzaldehyde, followed by a [[Reformatsky reaction|Reformatskii reaction]] of the protected aldehyde with ethyl bromoacetate/Zn to give the expected β-hydroxy ester. This intermediate was converted to the corresponding acylhydrazide with hydrazine, then the acylhydrazide reacted with HNO<sub>2</sub>, ultimately yielding the ''p''-benzyloxy-phenyloxazolidone. This was ''N''-methylated using [[dimethyl sulfate]], then hydrolyzed and ''O''-debenzylated by heating with HCl, to give racemic synephrine.<ref>{{cite journal | author = Bergmann E. D., Sulzbacher M. | year = 1951 | title = A new synthesi of 1-(''m''- and ''p''-hydroxyphenyl)-2-methylaminoethanol (''m''- and ''p''-sympathol) | journal = The Journal of Organic Chemistry | volume = 16 | pages = 84–89 | doi = 10.1021/jo01141a013 }}</ref>

===Structural relationships===
Much reference has been made in the literature (both lay and professional) of the structural kinship of synephrine with [[ephedrine]], or with [[phenylephrine]], often with the implication that the perceived similarities in structure should result in similarities in pharmacological properties. However, from a chemical perspective, synephrine is also related to a very large number of other drugs whose structures are based on the phenethylamine skeleton, and although some properties are common, others are not, making unqualified comparisons and generalizations inappropriate.

Thus, replacement of the ''N''-[[methyl]] group in synephrine with a hydrogen atom gives [[octopamine]]; replacement of the β-[[hydroxyl|hydroxy]] group in synephrine by a H atom gives [[N-methyltyramine|''N''-methyltyramine]]; replacement of the synephrine [[phenol]]ic 4-OH group by a –H gives [[halostachine]].

If the synephrine phenolic 4-OH group is shifted to the ''meta''-, or 3-position on the benzene ring, the compound known as phenylephrine (or ''m''-synephrine, or "Neo-synephrine") results; if the same group is shifted to the ''ortho''-, or 2-position on the ring, ''o''-synephrine results.

Addition of another phenolic –OH group to the 3-position of the benzene ring produces the [[neurotransmitter]] [[epinephrine]]; addition of a [[methyl]] group to the α-position in the side-chain of synephrine gives [[oxilofrine]] (methylsynephrine). Four stereoisomers (two pairs of enantiomers) are possible for this substance.

Extension of the synephrine ''N''-methyl substituent by one [[methylene bridge|methylene]] unit to an ''N''-[[ethyl group|ethyl]] gives the [[hypotensive]] experimental drug "Sterling #573"/"Aethyl-Sympatol".<ref>{{cite journal | author = Lands A. M., Rickards E. E., Nash V. L., Hooper K. Z. | year = 1947 | title = The pharmacology of vasodepressor compounds structurally related to the sympathomimetic amines | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 89 | issue = 4| pages = 297–305 | pmid = 20295509 }}</ref><ref>{{cite journal | author = Unna K | year = 1951 | title = Pharmakologische Untersuchungen über neue Sympatolabkömmlinge | journal = Naunyn-Schmiedebergs Archiv für Experimentelle Pathologie und Pharmakologie | volume = 213 | pages = 207–234 | doi = 10.1007/bf02432757 | s2cid = 30482120 }}</ref>

The above structural relationships all involve a change at ''one'' position in the synephrine molecule, and numerous other similar changes, many of which have been explored, are possible. However, the structure of ephedrine differs from that of synephrine at ''two'' different positions: ephedrine has no substituent on the phenyl ring where synephrine has a 4-OH group, and ephedrine has a methyl group on the position α- to the N in the side-chain, where syneprine has only a H atom. Furthermore, "synephrine" exists as either of two enantiomers, while "ephedrine" exists as one of four different enantiomers; there are, in addition, racemic mixtures of these enantiomers.

The main differences of the synephrine isomers compared for example to the [[ephedrine]]s are the hydroxy-substitutions on the benzene ring. Synephrines are direct sympathomimetic drugs while the ephedrines are both direct and indirect sympathomimetics. One of the main reasons for these differential effects is the obviously increased polarity of the hydroxy-substituted phenyl ethyl amines which renders them less able to penetrate the blood-brain barrier as illustrated in the examples for tyramine and the amphetamine analogs.<ref>{{cite journal | author = McCulloch J, Deshmukh VD, Harper AM | year = 1978 | title = Indirect sympathomimetic agents and cerebral blood flow and metabolism | journal = European Journal of Pharmacology | volume = 47 | issue = 1| pages = 11–8 | pmid = 412682 | doi = 10.1016/0014-2999(78)90368-0 }}</ref>

==Pharmacology==

===Synopsis===
Classical pharmacological studies on animals and isolated animal tissues showed that the principal actions of parenterally-administered synephrine included raising blood-pressure, dilating the pupil, and constricting peripheral blood vessels.

There is now ample evidence<sup>(what evidence?)</sup> that synephrine produces most of its biological effects by acting as an [[agonist]] (i.e. stimulating) at adrenergic receptors, with a distinct preference for the α<sub>1</sub> over the  α<sub>2</sub> sub-type. However, the potency of synephrine at these receptors is relatively low (i.e. relatively large concentrations of the drug are required to activate them). The potency of synephrine at adrenergic receptors of the β-class (regardless of sub-type) is much lower than at α-receptors. There is some evidence that synephrine also has weak activity at [[5-HT receptors]], and that it interacts with [[TAAR1]] (trace amine-associated receptor 1).

In common with virtually all other simple phenylethanolamines (β-hydroxy-phenethylamines), the (''R'')-(−)-, or l-, enantiomer of synephrine is more potent than the (''S'')-(+)-, or d-, enantiomer in most, but not all preparations studied. However, the majority of studies have been conducted with a racemic mixture of the two enantiomers.

Since the details regarding such variables as test species, receptor source, route of administration, drug concentration, and stereochemical composition are important but often incomplete in other Reviews and Abstracts of research publications, many are provided in the more technical review below, in order to support as fully as possible the broad statements made in this Synopsis.

===Pharmacology research===
Pharmacological studies on synephrine date back to the late 1920s, when it was observed that injected synephrine raised blood pressure, constricted peripheral blood vessels, dilated pupils, stimulated the uterus, and relaxed the intestines in experimental animals.<ref name = Las/><ref>{{cite journal | author = Ehrismann O., Maloff G. | year = 1928 | title = Über zwei Gifte der Adrenalingruppe (''p''-Oxyphenyläthanolmethylamin und sein Keton | journal = Naunyn-Schmiedebergs Archiv für Experimentelle Pathologie und Pharmakologie | volume = 136 | issue = 3–4| pages = 172–184 | doi = 10.1007/bf01862149 | s2cid = 21414110 }}</ref><ref>G. Kuschinsky (1930)). "Untersuchungen über Sympatol, einen adrenalinähnlichen Körper." ''Naunyn-Schmiedebergs Archiv für Experimentelle Pathologie und Pharmakologie'' '''156''' 290 - 308.</ref> Representative of this early work is the paper by Tainter and Seidenfeld, who were the first researchers to systematically compare the different effects of the two synephrine enantiomers, d- and l- synephrine, as well as of the racemate, d,l-synephrine, in various animal assays.<ref name = Tain/>
In experiments on anesthetized cats, Tainter and Seidenfeld confirmed earlier reports of the increase in blood pressure produced by intravenous doses of synephrine, showing that the median [[pressor]] doses for the isomers were: l-synephrine: 0.5&nbsp;mg/kg; d,l-synephrine: 1.0&nbsp;mg/kg; and d-synephrine: 2–20&nbsp;mg/kg. These effects lasted 2–3 minutes, peaking at ~30 seconds after administration. l-Synephrine was thus the more potent enantiomer, with about 1/60x the potency of the standard pressor l-epinephrine in the same assay.
A later study, by Lands and Grant, showed that a dose of ~0.6&nbsp;mg/kg of racemic synephrine, given intravenously to anesthetized dogs, produced a rise in blood pressure of 34&nbsp;mmHg lasting 5–10 minutes, and estimated that this pressor activity was about 1/300x that of epinephrine.<ref name = Lands>{{cite journal | author = Lands A. M., Grant J. I. | year = 1952 | title = The vasopressor action and toxicity of cyclohexylethylamine derivatives | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 106 | issue = 3| pages = 341–345 | pmid = 13000630 }}</ref>

Using cats and dogs, Tainter and Seidenfeld observed that neither d- nor l-synephrine caused any changes in the tone of normal [[bronchi]], ''in situ'', even at "maximum" doses. Furthermore, the marked brocho-constriction produced by injections of [[histamine]] was not reversed by either l-synephrine  or d,l-synephrine.<ref name = Tain/>

In experiments with isolated sheep [[carotid]] artery, d-, l- and d,l-synephrine all showed some [[vasoconstrictor]] activity: l-synephrine was the most potent, producing strong contractions at a concentration of 1:10000.{{efn|~ 5 x 10<sup>−4</sup>M.}} d-Synephrine was about 1/2 as potent as the l-isomer, but d,l-synephrine (which would have been expected to have a potency of 1/2 that of l-synephrine even if the d-isomer were completely inactive) did not produce significant and irregular contractions until a concentration of 1:2500{{efn|~ 2 x 10<sup>−3</sup>M.}}had been reached, implying an inhibitory interaction between the two enantiomers.<ref name = Tain/>

Qualitatively similar results were obtained in a rabbit ear preparation: 25&nbsp;mg l-synephrine produced significant (50%) vasoconstriction, while the same concentration of d-synephrine elicited essentially no response. In contrast, d,l-synephrine did not produce any constriction up to 25&nbsp;mg, but 25 – 50&nbsp;mg caused a relaxation of the blood vessels, which again suggested that the d-isomer might be inhibiting the action of the l-isomer.<ref name = Tain/>

Experiments on strips of rabbit [[duodenum]] showed that l-synephrine caused a modest reduction in contractions at a concentration of 1:17000,{{efn|~ 3 × 10<sup>−4</sup>M.}} but that the effects of the d- and d,l- forms were much weaker.<ref name = Tain/>

Racemic synephrine, given intramuscularly, or by instillation, was found to significantly reduce the inflammation caused by instillation of [[mustard oil]] into the eyes of rabbits.<ref name = Tain/>

Subcutaneous injection of racemic synephrine into rabbits was reported to cause a large rise in [[blood sugar]].<ref name = Hart/>

In experiments on anesthetized cats, Papp and Szekeres found that synephrine (stereochemistry unspecified) raised the thresholds for auricular and ventricular [[fibrillation]], an indication of [[anti-arrhythmic]] properties.<ref>{{cite journal | author = Papp L. Szekeres | year = 1968 | title = The arrhythmogenic action of sympathomimetic amines | journal = European Journal of Pharmacology | volume = 3 | issue = 1| pages = 4–14 | doi = 10.1016/0014-2999(68)90042-3 | pmid = 4968334 }}</ref>

Evidence that synephrine might have some [[central nervous system|central]] effects comes from the research of Song and co-workers, who studied the effects of synephrine in mouse models{{efn|Tail suspension and enforced swimming.}} of anti-depressant activity.<ref>{{cite journal | author = Song D.-K., Suh H.-W., Jung J.-S., Wie M.-B., Son K.-H., Kim Y.-H. | year = 1996 | title = Antidepressant-like effects of ''p''-synephrine in mouse models of immobility tests | journal = Neuroscience Letters | volume = 214 | issue = 2–3| pages = 107–110 | doi = 10.1016/0304-3940(96)12895-0 | pmid = 8878095 | s2cid = 28440606 }}</ref> These researchers observed that oral doses of 0.3 – 10&nbsp;mg/kg of racemic synephrine were effective in shortening the duration of immobility{{efn|Ostensibly correlated to anti-depressant activity.}} produced in the assays, but did not cause any changes in spontaneous motor activity in separate tests. This characteristic immobility could be counteracted by the pre-administration of [[prazosin]].{{efn|An adrenergic antagonist selective for α<sub>1</sub> receptors.}}
Subsequent experiments using the individual enanatiomers of synephrine revealed that although the d-isomer significantly reduced the duration of immobility in the tail suspension test, at an oral dose of 3&nbsp;mg/kg, the l-isomer had no effect at the same dose.
In mice pre-treated with [[reserpine]],{{efn|Reversal of reserpine-induced hypothermia by a drug is a classical test for potential anti-depressant properties.}} an oral dose of 0.3&nbsp;mg/kg d-synephrine significantly reversed the [[hypothermia]], while l-synephrine required a dose of 1&nbsp;mg/kg to be effective.
Experiments with slices of [[cerebral cortex]] taken from rat brain showed that d-synephrine inhibited the uptake of [<sup>3</sup>H]-norepinephrine with an IC<sub>50</sub> = 5.8 μM; l-synephrine was less potent (IC<sub>50</sub> = 13.5 μM).
d-Synephrine also competitively inhibited the binding of [[nisoxetine]]{{efn|A selective inhibitor of the [[norepinephrine transporter]].}} to rat brain cortical slices, with a K<sub>i</sub> = 4.5 μM; l-synephrine was less potent (K<sub>i</sub> = 8.2 μM).
In experiments on the release of [<sup>3</sup>H]-norepinephrine from rat brain cortical slices, however, the l-isomer of synephrine was a more potent enhancer of the release (EC<sub>50</sub> = 8.2 μM) than the d-isomer (EC<sub>50</sub> = 12.3 μM). This enhanced release by l-synephrine was blocked by nisoxetine.<ref>{{cite journal | author = Kim K.-W., Kim H.-D., Jung J.-S., Woo R.-S., Kim H.-S., Suh H.-W., Kim Y.-H., Song D.-K. | year = 2001 | title = Characterization of antidepressant-like effects of ''p''-synephrine stereoisomers | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 364 | issue = 1| pages = 21–26 | doi = 10.1007/s002100100416 | pmid = 11485034 | s2cid = 12625027 }}</ref>

Burgen and Iversen, examining the effect of a broad range of phenethylamine-based drugs on [<sup>14</sup>C]-norepinephrine-uptake in the isolated rat heart, observed that racemic synephrine{{efn|Referred to here as "oxedrine".}} was a relatively weak inhibitor (IC<sub>50</sub> = 0.12 μM) of the uptake.<ref>{{cite journal | author = Burgen A. S. V., Iversen L. L. | year = 1964 | title = The inhibition of noradrenaline uptake by sympathomimetic amines in the rat isolated heart | journal = British Journal of Pharmacology and Chemotherapy | volume = 25 | issue = 1| pages = 34–49 | doi = 10.1111/j.1476-5381.1965.tb01754.x | pmid = 19108208 | pmc = 1510671 }}</ref>

Another receptor-oriented study by Wikberg revealed that synephrine ([[stereochemistry]] unspecified) was a more potent agonist at guinea pig [[aorta]] α<sub>1</sub> receptors (pD<sub>2</sub> = 4.81) than at [[ileum]] α<sub>2</sub> receptors (pD<sub>2</sub> = 4.48), with a relative affinity ratio of α<sub>2</sub>/α<sub>1</sub> = 0.10. Although clearly indicating a selectivity of synephrine for α<sub>1</sub> receptors, its potency at this receptor sub-class is still relatively low, in comparison with that of phenylephrine (pD<sub>2</sub> at α<sub>1</sub> = 6.32).<ref>{{cite journal | author = Wikberg J. E. S. | year = 1978 | title = Pharmacological classification of adrenergic α receptors in the guinea pig | journal = Nature | volume = 273 | issue = 5658| pages = 164–166 | doi = 10.1038/273164a0 | pmid = 25390 | bibcode = 1978Natur.273..164W | s2cid = 4278917 }}</ref>

Brown and co-workers examined the effects of the individual enantiomers of synephrine on α<sub>1</sub> receptors in rat [[aorta]], and on α<sub>2</sub> receptors in rabbit [[Great saphenous vein|saphenous]] vein. In the aorta preparation, l-synephrine gave a pD<sub>2</sub> = 5.38 (potency relative to norepinephrine = 1/1000), while d-synephrine had a pD<sub>2</sub> = 3.50 (potency relative to norepinephrine = 1/50000); in comparison, l-phenylephrine had pD<sub>2</sub> = 7.50 (potency relative to norepinephrine ≃ 1/6). No antagonism of norepinephrine was produced by concentrations of l-synephrine up to 10<sup>−6</sup> M. In the rabbit saphenous assay, the pD<sub>2</sub> of l-synephrine was 4.36 (potency relative to norepinephrine ≃ 1/1700), and that of d-synephrine was < 3.00; in comparison, l-phenylephrine had pD<sub>2</sub> = 5.45 (potency relative to norepinephrine ≃ 1/140). No antagonism of norepinephrine was produced by concentrations of l-synephrine up to 10<sup>−5</sup> M.<ref name = Brown>{{cite journal | author = 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. | year = 1988 | title = Activities of octopamine and synephrine stereoisomers on α-adrenoceptors | journal = British Journal of Pharmacology | volume = 93 | issue = 2| pages = 417–429 | doi = 10.1111/j.1476-5381.1988.tb11449.x | pmid = 2833972 | pmc = 1853804 }}</ref>

A study of the effects of synephrine (stereochemistry unspecified) on strips of guinea pig aorta and on the field-stimulated guinea pig [[ileum]] showed that synephrine had an agonist potency of −logK<sub>a</sub> = 3.75 in the aorta assay. In comparison, epinephrine had a potency of −logK<sub>a</sub> = 5.70. There was no significant effect on the ileum at synephrine concentrations up to about 2 × 10<sup>−4</sup> M, indicating selectivity for the α<sub>1</sub> receptor, but relatively low potency.<ref>{{cite journal | author = Ruffolo R. R., Waddell J. E. | year = 1983 | title = Aromatic and benzylic hydroxyl substitution of imidazolines and phenethylamines: differences in activity at alpha-1 and alpha-2 adrenergic receptors | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 224 | issue = 3| pages = 559–566 | pmid = 6131121 }}</ref>

In binding experiments with central adrenergic receptors, using a preparation from rat cerebral cortex, l-synephrine had pIC<sub>50</sub> = 3.35, and d-synephrine had pIC<sub>50</sub> = 2.42 in competition against [<sup>3</sup>H]-[[prazosin]] (standard α<sub>1</sub> ligand); against [<sup>3</sup>H]-[[yohimbine]] (standard α<sub>2</sub> ligand), l-synephrine showed a pIC<sub>50</sub> = 5.01, and d-synephrine showed a pIC<sub>50</sub> = 4.17.<ref name = Brown/>

Experiments conducted by Hibino and co-workers also showed that synephrine (stereochemistry unspecified) produced a dose-dependent constriction of isolated rat aorta strips, in the concentration range 10<sup>−5</sup>–3 × 10<sup>−6</sup> M. This constriction was found to be competitively antagonized by prazosin (a standard α<sub>1</sub> antagonist) and [[ketanserin]],{{efn|A drug often used as a selective 5-HT<sub>2A</sub> antagonist.}} with prazosin being the more potent antagonist (pA<sub>2</sub> = 9.38, vs pA<sub>2</sub> = 8.23 for ketanserin). Synephrine constrictions were also antagonized by [[BRL-15,572]],{{efn|Used here as a selective 5-HT<sub>1D</sub> antagonist.}} but not by [[SB-216,641]] (used here as a selective 5-HT<sub>1B</sub> antagonist), or by [[propranolol]] (a common β antagonist).<ref>{{cite journal | author = Hibino T., Yuzurihara M., Kase Y., Takeda A. | year = 2009 | title = Synephrine, a component of Evodiae Fructus, constricts isolated rat aorta via adrenergic and serotonergic receptors | journal = Journal of Pharmacological Sciences | url = https://www.jstage.jst.go.jp/article/jphs/111/1/111_09077FP/_pdf | volume = 111 | issue = 1| pages = 73–81 | doi = 10.1254/jphs.09077fp | pmid = 19721332 | doi-access = free }}</ref>

In studies on guinea pig [[Atrium (heart)|atria]] and [[Vertebrate trachea|trachea]], Jordan and co-workers also found that synephrine had negligible activity on β<sub>1</sub> and β<sub>2</sub> receptors, being about 40000x less potent than norepinephrine.<ref>{{cite journal | author = Jordan R., Midgley J. M., Thonoor C. M., Williams C. M. | year = 1987 |title=Beta-adrenergic activities of octopamine and synephrine stereoisomers on guinea-pig isolated atria and trachea | journal = J. Pharm. Pharmacol. | volume = 39 | issue = 9| pages = 752–754 | doi = 10.1111/j.2042-7158.1987.tb06986.x | pmid = 2890747 | s2cid = 38557968 }}</ref>

Experiments with cultured [[adipocytes|white fat cells]] from several animal species, including human, by Carpéné and co-workers showed that racemic synephrine produced [[lipolysis|lipolytic]] effects, but only at high concentrations (0.1-1 mM). The potency, expressed in terms of pD<sub>2</sub> of synephrine in these species was as follows: rat: 4.38; hamster: 5.32; guinea pig: 4.31; human: 4.94. In comparison, [[isoprenaline]] had a pD<sub>2</sub> = 8.29 and norepinephrine had pD<sub>2</sub> = 6.80 in human white fat cells. The lipolytic effect of 1 mM/L of synephrine on rat white fat cells was antagonized by various β-antagonists with the following inhibitory concentrations (IC<sub>50</sub>): [[bupranolol]]:{{efn|Used as a non-selective β-antagonist}} 0.11 μM; CGP-20,712A (β<sub>1</sub> antagonist): 6.09 μM; ICI-118,551 (β<sub>2</sub> antagonist): 3.58 μM; SR-5923A (β<sub>3</sub> antagonist): 17 μM.<ref>{{cite journal | author = Carpéné C., Galitzky J., Fontana E., Atgié C., Lafontan M., Berlan M. | year = 1999 | title = Selective activation of β3-adrenoceptors by octopamine: comparative studies in mammalian fat cells | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 359 | issue = 4| pages = 310–321 | doi = 10.1007/pl00005357 | pmid = 10344530 | s2cid = 34370879 }}</ref>

The binding of racemic synephrine to cloned human adrenergic receptors has been examined: Ma and co-workers found that synephrine bound to α<sub>1A</sub>, α<sub>2A</sub> and α<sub>2C</sub> with low affinity (pK<sub>i</sub> = 4.11 for α<sub>1A</sub>; 4.44 for α<sub>2A</sub>; 4.61 for α<sub>2C</sub>). Synephrine behaved as a [[partial agonist]] at α<sub>1A</sub> receptors, but as an antagonist at α<sub>2A</sub> and α<sub>2C</sub> sub-types.<ref>{{cite journal | author = Ma G., Bavadeka S. A., Schaneberg B. T., Khan I. A., Feller D. R. | year = 2010 | title = Effects of synephrine and beta-phenylephrine on human alpha-adrenoreceptor subtypes | journal = Planta Medica | volume = 76 | issue = 10| pages = 981–986 | doi = 10.1055/s-0029-1240884 | pmid = 20217639 | s2cid = 41387315 }}</ref>

Racemic 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> although its potency at the human TAAR1 is relatively low (EC<sub>50</sub> = 23700 nM; E<sub>max</sub> = 81.2%).<ref>{{cite journal | author = Wainscott D. B., Little S. P., Yin T., Tu Y., Rocco V. P., He J. X., Nelson D. L. | year = 2007 | title = Pharmacologic characterization of the cloned human Trace Amine-Associated Receptor1 (TAAR1) and evidence for species differences with the rat TAAR1 | journal = Journal of Pharmacology and Experimental Therapeutics | volume = 320 | issue = 1| pages = 475–485 | doi = 10.1124/jpet.106.112532 | pmid = 17038507 | s2cid = 10829497 }}</ref>

==Pharmacokinetics==
The pharmacokinetics of synephrine were studied by Hengstmann and Aulepp, who reported a peak plasma concentration at 1–2 hours, with an elimination half-life (T<sub>1/2</sub>) of ~ 2 hours.<ref>{{cite journal | author = Hengstmann J. H., Aulepp H. | year = 1978 | title = Pharmacokinetics and metabolism of <sup>3</sup>H-synephphrine | journal = Arzneimittelforschung | volume = 28 | pages = 2326–2331 }}</ref>

==Metabolism==
Studies of the metabolism of synephrine by [[monoamine oxidase]]s derived from rat brain [[mitochondria]] showed that synephrine was a substrate for [[deamination]] by both [[MAO-A]] and [[MAO-B]], with K<sub>m</sub> = 250 μM and V<sub>max</sub> = 32.6 nM/mg protein/30 minutes; there was some evidence for preferential deamination by MAO-A.<ref>{{cite journal | author = Suzuki O., Matsumoto T., Oya M., Katsumata Y. | year = 1979 | title = Oxidation of synephrine by type A and type B monoamine oxidase | journal = Experientia | volume = 35 | issue = 10| pages = 1283–1284 | doi = 10.1007/bf01963957 | pmid = 499398 | s2cid = 6129913 }}</ref>

==Effects in humans==
{{more medical citations needed|section|date=January 2014}}
A number of studies of the effects of synephrine in humans, most of them focusing on its cardiovascular properties, have been performed since its introduction as a synthetic drug around 1930.<ref name = Stock/><ref>U. von Euler and G. Liljestrand (1929). ''Skand. Arch. Physiol.'' '''55''' 1.</ref><ref>{{cite journal | author = Pohle F., Sarre H. | year = 1940 | title = Der Wirkungsmechanismus eines neuen peripheren Kreislaufmittels im Vergleich mit Veritol und Sympatol beim Menschen | journal = Naunyn-Schmiedebergs Archiv für Experimentelle Pathologie und Pharmakologie | volume = 196 | issue = 2–5| pages = 408–430 | doi = 10.1007/bf01861124 | s2cid = 34593711 }}</ref><ref>{{cite journal | author = Heim F | year = 1948 | title = Über die Blutdruckwirksamkeit von Sympatol an Menschen nach Vorbehandlung mit Ephedrin, Veritol und Pervitin | journal = Naunyn-Schmiedebergs Archiv für Experimentelle Pathologie und Pharmakologie | volume = 205 | issue = 4–5 | pages = 470–479 | doi = 10.1007/bf00246173 | s2cid = 25139273 }}</ref><ref>{{cite journal | author = Nathanson M. H., Miller H. | year = 1950 | title = The effect of new drugs on the rhythmic function of the heart | journal = Calif. Med. | volume = 72 | issue = 4| pages = 215–221 | pmid = 18731684 | pmc = 1520549 }}</ref><ref name = Hoff>{{Cite journal |pmid = 4096743|year = 1985|last1 = Hofstetter|first1 = R.|last2 = Kreuder|first2 = J.|last3 = von Bernuth|first3 = G.|title = The effect of oxedrine on the left ventricle and peripheral vascular resistance|journal = Arzneimittel-Forschung|volume = 35|issue = 12|pages = 1844–6}}</ref> The paper by Stockton and co-workers is representative, describing the effects of racemic synephrine in humans with particular attention to differences resulting from different routes of administration. Thus, it was shown by these investigators that ''intramuscular'' injections (average effective dose = 200&nbsp;mg) of the drug produced an increase in [[systole (medicine)|systolic]] blood pressure and pulse rate, without affecting the [[diastolic]] pressure. The blood pressure increase reached a maximum (~25&nbsp;mmHg) in 5 minutes following the injection, then gradually returned to normal over the course of 1 hour. Doses of drug greater than 200&nbsp;mg caused side-effects such as heart palpitations, headache, sweating, and feelings of apprehension. When given ''intravenously'', doses of 25–50&nbsp;mg sufficed to produce a mean maximum increase in the blood pressure of 29&nbsp;mmHg in 2 minutes, and a return to baseline within 30 minutes. Respiration was generally not affected during these experiments. ''Subcutaneous'' administration of synephrine in doses ≤ 200&nbsp;mg had no effects on blood pressure or pulse rate. ''Oral'' doses of 500–1500&nbsp;mg of the drug did not affect blood pressure or respiration, but pulse rate was increased by ~12%, and the highest doses caused nausea and vomiting.<ref name = Stock/>

The i.m. administration of 75–500&nbsp;mg of synephrine did not relieve acute [[asthma]] attacks, contradicting an earlier claim.<ref>{{cite journal | author = Tiefensee K | year = 1932 | title =  Therapy of bronchial asthma with adrenalin and the adrenalin derivatives ephedrine and sympatol| journal = Journal of Allergy | volume = 4 | page = 81 | doi = 10.1016/s0021-8707(32)90053-7 }}</ref> However, the topical application of 1–3% solutions of the drug to the [[mucous membrane of nose|nasal mucosa]] of patients with [[sinusitis]] did produce a beneficial constriction without local irritation.<ref name = Stock/>

Administration of synephrine by continuous intravenous infusion, at the rate of 4&nbsp;mg/minute, significantly increased mean arterial and [[systole (medicine)|systolic]] pressure, but [[diastole|diastolic]] pressure and heart rate were unaltered.;<ref name = Hoff/> further details of this investigation are summarized in a review by Fugh-Berman and Myers.<ref>{{Cite journal | doi=10.1177/153537020422900802| title=Citrus aurantium, an Ingredient of Dietary Supplements Marketed for Weight Loss: Current Status of Clinical and Basic Research| year=2004| last1=Fugh-Berman| first1=Adriane| last2=Myers| first2=Adam| journal=Experimental Biology and Medicine| volume=229| issue=8| pages=698–704| pmid=15337824| s2cid=35942851}}</ref>

There are a number of studies, references to many of which may be found in the review by Stohs and co-workers<ref name = Stohs>{{cite journal | author = Stohs S. J., Preuss H. G., Shara M. | year = 2011 | title = The Safety of ''Citrus aurantium'' (Bitter Orange) and its primary protoalkaloid ''p''-synephrine | journal = Phytotherapy Research | volume = 25 | issue = 10| pages = 1421–1428 | doi = 10.1002/ptr.3490 | pmid = 21480414 | s2cid = 32789083 }}</ref> dealing with the effects produced by dietary supplements and herbal medications that contain synephrine as only one of many different chemical ingredients. These are outside the scope of the present article (see also the "[[#Safety/Efficacy/Controversy|Safety/Efficacy/Controversy]]" sub-section).

==Toxicology==
The acute toxicities of racemic synephrine in different animals, reported in terms of "maximum tolerated dose" after s.c administration, were as  follows: mouse: 300&nbsp;mg/kg; rat: 400&nbsp;mg/kg; guinea pig: 400&nbsp;mg/kg. "Lethal doses", given s.c., were found to be: mouse: 400&nbsp;mg/kg; rat: 500&nbsp;mg/kg; guinea pig: 500&nbsp;mg/kg.<ref name = Las/> Another study of this compound,{{efn|Referred to as "Sympathol".}} administered i.v. in mice, gave an LD<sub>50</sub> = 270&nbsp;mg/kg.<ref name = Lands/>

The "subchronic toxicity" of synephrine was judged to be low in mice, after administration of oral doses of 30 and 300&nbsp;mg/kg over a period of 28 days. Generally, this treatment did not result in significant alterations in biochemical or hematological parameters, nor in relative organ weights, but some changes were noted in [[glutathione]] (GSH) concentration, and in the activity of [[glutathione peroxidase]] (GPx).<ref>{{cite journal | author = Arbo M. D., Schmitt G. C., Limberger M. F., Charão M. F., Moro Â. M., Ribeiro G. L., Dallegrave E., Garcia S. C., Leal M. B., Limberger R. P. | year = 2009 | title = Subchronic toxicity of ''Citrus aurantium'' L. (Rutaceae) extract and ''p''-synephrine in mice | journal = Regulatory Toxicology and Pharmacology | volume = 54 | issue = 2| pages = 114–117 | doi = 10.1016/j.yrtph.2009.03.001 | pmid = 19275924 }}</ref>

==Safety/efficacy/controversy==
There exists considerable controversy about the safety and/or efficacy of ''synephrine-containing preparations'', which are often confused with synephrine alone, sometimes with ''m''-synephrine.<ref name = Blum/><ref name="G. Rossato, V. M 2011"/><ref name = Stohs/><ref>{{cite journal | author = Nasir J. M., Durning S. J., Ferguson M., Barold H. S., Haigney M. C. | year = 2004 | title = Exercise-induced syncope associated with QT prolongation and Ephedra-free Xenadrine | journal = Mayo Clinic Proceedings | volume = 79 | issue = 8| pages = 1059–1062 | doi = 10.4065/79.8.1059 | pmid = 15301335 | doi-access = free }}</ref><ref>{{cite journal | author = Bouchard N., Hoffman R. S. | year = 2004 | title = Synephrine is not Neo-Synephrine | journal = Mayo Clinic Proceedings | volume = 79 | issue = 12| pages = 1589–1590 | doi = 10.4065/79.12.1589-b | pmid = 15595351 | doi-access = free }}</ref><ref>{{cite journal | author = Bent S., Padula A., Neuhaus J. | year = 2004 | title = Safety and efficacy of ''Citrus aurantium'' for weight loss | journal = The American Journal of Cardiology | volume = 94 | issue = 10| pages = 1359–1361 | doi = 10.1016/j.amjcard.2004.07.137 | pmid = 15541270 }}</ref><ref>{{cite journal | author = Bouchard N. C., Howland M. A., Greller H. A., Hoffman R. S., Nelson L. S. | year = 2005 | title = Ischemic stroke associated with use of an Ephedra-free dietary supplement containing synephrine | journal = Mayo Clinic Proceedings | volume = 80 | issue = 4| pages = 541–545 | doi = 10.4065/80.4.541 | pmid = 15819293 | doi-access = free }}</ref><ref>{{cite journal | author = Firenzuoli F., Gori L., Galapai C. | year = 2005 | title = Adverse reaction to an adrenergic herbal extract (''Citrus aurantium'') | journal = Phytomedicine | volume = 12 | issue = 3| pages = 247–248 | doi = 10.1016/j.phymed.2004.02.005 | pmid = 15830849 }}</ref><ref>{{cite journal | author = Haaz S., Fontaine K. R., Cutter G., Limdi N., Perumean-Chaney S., Allison D. B. | year = 2006 | title = ''Citrus aurantium'' and synephrine alkaloids in the treatment of overweight and obesity: an update | journal = Obesity Reviews | volume = 7 | issue = 1| pages = 79–88 | doi = 10.1111/j.1467-789x.2006.00195.x | pmid = 16436104 | s2cid = 13842012 }}</ref><ref>{{cite journal | author = Thomas J. E., Munir J. A., McIntyre P. Z., Ferguson M. A. | year = 2009 | title = STEMI in a 24-year-old man after use of a synephrine-containing dietary supplement: a case report and review of the literature | journal = Texas Heart Institute Journal | volume = 36 | issue = 6| pages = 586–90 | pmid = 20069086 | pmc = 2801940 }}</ref><ref>{{cite journal | author = Thomas J. E., Munir J. A., McIntyre P. Z., Ferguson M. A. | year = 2010 | title = Lack of evidence that ''p''-synephrine is responsible for STEMI | journal = Texas Heart Institute Journal | volume = 37 | issue = 3| pages = 383–384 | pmid = 20548833 | pmc = 2879205 }}</ref><ref>{{cite journal | author = Stohs S. J. | year = 2010 | title = Assessment of the adverse event reports associated with ''Citrus aurantium'' (bitter orange) from April 2004 to October 2009 | journal = Journal of Functional Foods | volume = 2 | issue = 4| pages = 235–239 | doi = 10.1016/j.jff.2010.10.003 }}</ref> Furthermore, this body of literature deals with mixtures containing synephrine as only one of several biologically active components, even, in some cases, without explicit confirmation of the presence of synephrine.

==Invertebrates==
In insects, synephrine has been found to be a very potent agonist at many invertebrate [[octopamine]] receptor preparations, and is even more potent than octopamine at a [[locust]] (''[[Schistocerca]] americana gregaria'') nerve-muscle preparation.<ref>{{cite journal | author = Evans P. D. | year = 1981 | title = Multiple receptor types for octopamine in the locust | journal = The Journal of Physiology | volume = 318 | pages = 99–122 | doi = 10.1113/jphysiol.1981.sp013853 | pmid = 6275071 | pmc = 1245480 }}</ref> Synephrine (racemic) is also more potent than octopamine (racemic) at inducing light-emission in the [[firefly]] (''[[Photinus]]'' species) light organ.<ref>{{cite journal | author = Carlson A. D. | year = 1968 | title = Effect of drugs on luminescence in larval fireflies | journal = The Journal of Experimental Biology | volume = 49 | issue = 1| pages = 195–199 | doi = 10.1242/jeb.49.1.195 | pmid = 4386272 }}</ref> Synephrine exhibits similarly high potency in stimulating [[adenylate cyclase]] activity and in decreasing clotting time in [[lobster]] (''[[Homarus americanus]]'') hematocytes.<ref>{{cite journal | author = Battelle A., Kravitz E. A. | year = 1978 | title = Targets of octopamine action in the lobster: cyclic nucleotide changes and physiological effects in hemolymph, heart and exoskeletal muscle | journal = J. Pharmacol. Exp. Ther. | volume = 205 | issue = 2| pages = 438–448 | pmid = 347053 }}</ref> Racemic synephrine was found to increase [[Cyclic adenosine monophosphate|cAMP]] in the abdominal epidermis of the blood-sucking bug, ''[[Rhodnius prolixus]]''.<ref>{{cite journal | author = Barrett M., Orchard I. | year = 1990 | title = Serotonin-induced elevation of cAMP levels in the epidermis of the blood-sucking bug, ''Rhodnius prolixus'' | journal = Journal of Insect Physiology | volume = 36 | issue = 9| pages = 625–633 | doi = 10.1016/0022-1910(90)90066-o | bibcode = 1990JInsP..36..625B }}</ref> Rachinsky reported that synephrine was equipotent with octopamine in stimulating JH ([[juvenile hormone]]) release in the [[corpora allata]] of [[honey bee]] (''[[Apis mellifera]]''),<ref>{{cite journal | author = Rachinsky A | year = 1994 | title = Octopamine and serotonin influence on ''corpora allata'' activity in honey bee (''Apis mellifera'') larvae | journal = Journal of Insect Physiology | volume = 40 | issue = 7| pages = 549–554 | doi = 10.1016/0022-1910(94)90141-4 | bibcode = 1994JInsP..40..549R }}</ref> but Woodring and Hoffmann found that synephrine had no effect on the synthesis of [[Juvenile hormone|JH III]], in ''in vitro'' preparations from the cricket, ''[[Gryllus bimaculatus]]''.<ref>{{cite journal | author = Woodring J., Hoffmann K. H. | year = 1994 | title = The effects of octopamine, dopamine and serotonin on juvenile hormone synthesis, In vitro, in the cricket, ''Gryllus bimaculatus'' | journal = Journal of Insect Physiology | volume = 40 | issue = 9| pages = 797–802 | doi = 10.1016/0022-1910(94)90009-4 | bibcode = 1994JInsP..40..797W }}</ref>

== Footnotes ==
{{notelist}}

== See also ==
* [[Halostachine]]
* [[Deterenol]]
* [[Octopamine]]

== References ==
{{Reflist}}

{{Neurotransmitters}}
{{Cardiac stimulants}}
{{Adrenergic receptor modulators}}
{{TAAR ligands}}
{{Phenethylamines}}

[[Category:Alpha-1 adrenergic receptor agonists]]
[[Category:Alkaloids found in Rutaceae]]
[[Category:Antihypotensive agents]]
[[Category:Human metabolites]]
[[Category:4-Hydroxyphenyl compounds]]
[[Category:Phenylethanolamines]]
[[Category:Phenethylamines]]
[[Category:Sympathomimetics]]
[[Category:TAAR1 agonists]]
[[Category:Trace amines]]