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.
Synephrine (or formerly Sympatol and oxedrine [BAN]) and
m-synephrine are known for their longer acting adrenergic effects
compared to norepinephrine. This substance is present at very low
concentrations in common foodstuffs such as orange juice and other
Citrus species) products, both of the "sweet" and "bitter"
variety. The preparations used in traditional Chinese medicine (TCM),
also known as Zhi Shi, 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 OTC drug. As a pharmaceutical,
m-synephrine 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, and rarely orally for the
treatment of bronchial problems associated with asthma and
It is important to distinguish 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.
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.
1 Natural occurrences
1.1 In Citrus
1.2 In humans and other animals
2 Presence in nutritional/dietary supplements
3 Pharmaceutical use
5.3 Structural relationships
6.2 Pharmacology research
9 Effects in humans
14 See also
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. A survey of the
distribution of synephrine amongst the higher plants was published in
1970 by Wheaton and Stewart. It has subsequently been detected in
Zanthoxylum species, all plants of the family
Trace levels (0.003%) of synephrine have also been detected in the
dried leaves of
Pogostemon cablin (patchouli, Lamiaceae). It is
also found in certain cactus species of the genera
However, this compound is found predominantly in a number of Citrus
species, including "bitter" and "sweet" orange varieties.
Extracts of unripe fruit from Asian cultivars of
(commonly known as "bitter" orange), collected in China, were reported
to contain synephrine levels of about 0.1–0.3%, or
~1–3 mg/g; Analysis of dried fruit of C. aurantium grown in
Italy showed a concentration of synephrine of ~1 mg/g, with peel
containing over three times more than the pulp.
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); from these results, it
was calculated that eating one "average" Tarocco orange would result
in the consumption of ~6 mg of synephrine.
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 mg/g–0.0009 mg/g[b] in those jams made from bitter
oranges, and levels of 0.05 mg/g–0.006 mg/g[c] of
synephrine in jams made from sweet oranges.
Synephrine has been found in marmalade made from
(Satsuma mandarin) obtained in Japan, at a concentration of
~0.12 mg/g (or about 2.4 mg/20g serving). Most of the
orange marmalades made in the US are produced using "sweet" oranges
(C. sinensis), whereas "bitter" or Seville oranges (C. aurantium) are
used for making the more traditional, bitterer marmalades in the
A sample of commercial Japanese C. unshiu juice was found to contain
~0.36 mg/g synephrine (or roughly 360 mg/L), while in
juice products obtained from a Satsuma mandarin variety grown in
California, levels of synephrine ranged from 55 to 160 mg/L .
Juices from "sweet" oranges purchased in Brazilian markets were found
to contain ~10–22 mg/L synephrine; commercial orange soft
drinks obtained on the Brazilian market had an average synephrine
content of ~1 mg/L. Commercial Italian orange juices
contained ~13–32 mg/L of synephrine
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 mg/L;[d] no synephrine was detected in juices from
grapefruit, lime, or lemon.
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 mg/L; Nova
tangerine (C. reticulata Tan.): ~78 mg/L; clementine (C.
clementina Tan.): ~115 mg/L; Meyer lemon (C. limon Tan.)
~3 mg/kg; Ugli tangelo (C. reticulata × C. paradisi)
~47 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).
Numerous additional comparable analyses of the synephrine content of
Citrus fruits and products derived from them may be found in the
In humans and other animals
Low levels of synephrine have been found in normal human
urine, as well as in other mammalian tissue. 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
A recent 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 ng/108 platelets,
compared to 0.33 ng/108 platelets in control subjects).
Earlier, the same research group had reported a normal human blood
plasma level of synephrine of 0.90–13.69 ng/mL.
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 stereoisomeric composition of synephrine extracted
from natural sources. Although it seems clear that synephrine is found
Citrus species which have been studied predominantly as the
l-isomer, low levels of d-synephrine have been detected in
juice and marmalade made from C. unshiu, and low levels (0.002%)
have been reported in fresh fruit from C. aurantium. 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. 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 Dolichothele
genus, under conditions that would be unlikely to cause a significant
amount of racemization.
The biosynthesis of synephrine in
Citrus species is believed to follow
the pathway: tyrosine → tyramine →
synephrine, involving the enzymes tyrosine decarboxylase in the first
step, tyramine N-methyltransferase in the second, and
N-methyl-tyramine-β-hydroxylase in the third. 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
Biosynthetic pathways for catecholamines and trace amines in the human
In humans, catecholamines and phenethylaminergic trace amines are
produced from the amino acid phenylalanine. Abbreviations: DBH:
Dopamine β-hydroxylase; AADC: Aromatic L-amino acid decarboxylase;
AAAH: (Biopterin-dependent) aromatic amino acid hydroxylase; COMT:
Catechol O-methyltransferase; PNMT: Phenylethanolamine
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
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). The concentration range found by
Santana and co-workers in five different supplements purchased in the
US was about 5–14 mg/g.
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. By 1930, Sympatol was referred to as a Boehringer
product, while one of the first US Patents describing its
preparation and use was assigned to Frederick Stearns & Co. in
1933. 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. 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)." 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. 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 mg, given intramuscularly, or subcutaneously.
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. 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 mg, by intravenous, intramuscular or subcutaneous
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
FDA "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 mg.
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 mg tid, and as a "conjunctival
decongestant" to be topically applied as a 0.5% solution. However,
no supporting references are provided.
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 over the
distinctions between p- and m-synephrine has even contaminated the
primary research literature.[e] 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 section).
In terms of molecular structure, synephrine has a phenethylamine
skeleton, with a phenolic hydroxy- group, an alcoholic 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) pKas for protonated synephrine are
9.55 (phenolic H) and 9.79 (ammonium H).
Common salts of racemic synephrine are its hydrochloride,
C9H13NO2.HCl, m.p. 150–152°, the oxalate
(C9H13NO2)2.C2H2O4, m.p. 221–222 °C, and the tartrate
(Sympatol), (C9H13NO2)2.C4H6O6, m.p. 188–190 °C.
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
(S)-configuration, and the levorotatory l-isomer to the
Racemic synephrine has been resolved using ammonium
3-bromo-camphor-8-sulfonate. The enantiomers were not
characterized as their free bases, but converted to the hydrochloride
salts, with the following properties:
(S)-(+)-C9H13NO2.HCl: m.p. 178 °C; [α] = +42.0°, c 0.1
(H2O); (R)-(−)-C9H13NO2.HCl: m.p. 176 °C; [α] =
−39.0°, c 0.2 (H2O)
(−)-Synephrine, as the free base isolated from a
Citrus source, has
m.p. 162–164 °C (with decomposition).[dead link]
The X-ray structure for synephrine has been determined.
Early and seemingly inefficient syntheses of synephrine were discussed
by Priestley and Moness, writing in 1940. 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 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 HNO2, 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.
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-hydroxy group in
synephrine by a H atom gives N-methyltyramine; replacement of the
synephrine phenolic 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
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 unit
to an N-ethyl gives the hypotensive experimental drug "Sterling
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
The main differences of the synephrine isomers compared for example to
the ephedrines 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.
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 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 α1 over the
α2 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
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
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.
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. 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. 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 mg/kg; d,l-synephrine: 1.0 mg/kg;
and d-synephrine: 2–20 mg/kg. These effects lasted 2–3
minutes, peaking at ~30 seconds after administration. l-
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 mg/kg of racemic
synephrine, given intravenously to anesthetized dogs, produced a rise
in blood pressure of 34 mmHg lasting 5–10 minutes, and
estimated that this pressor activity was about 1/300x that of
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.
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.[f] 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[g]had been reached, implying an inhibitory
interaction between the two enantiomers.
Qualitatively similar results were obtained in a rabbit ear
preparation: 25 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 mg, but 25 – 50 mg
caused a relaxation of the blood vessels, which again suggested that
the d-isomer might be inhibiting the action of the l-isomer.
Experiments on strips of rabbit duodenum showed that l-synephrine
caused a modest reduction in contractions at a concentration of
1:17000,[h] but that the effects of the d- and d,l- forms were much
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.
Subcutaneous injection of racemic synephrine into rabbits was reported
to cause a large rise in blood sugar.
In experiments on anesthetized cats, Papp and Szekeres found that
synephrine (stereochemistry unspecified) raised the thresholds for
auricular and ventricular fibrillation, an indication of
Evidence that synephrine might have some central effects comes from
the research of Song and co-workers, who studied the effects of
synephrine in mouse models[i] of anti-depressant activity. These
researchers observed that oral doses of 0.3 – 10 mg/kg of
racemic syephrine were effective in shortening the duration of
immobility[j] 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.[k] 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 mg/kg, the l-isomer had no effect at the same
dose. In mice pre-treated with reserpine,[l] an oral dose of
0.3 mg/kg d-synephrine significantly reversed the hypothermia,
while l-synephrine required a dose of 1 mg/kg to be effective.
Experiments with slices of cerebral cortex taken from rat brain showed
that d-synephrine inhibited the uptake of [3H]-norepinephrine with an
IC50 = 5.8 μM; l-synephrine was less potent (IC50 = 13.5 μM).
Synephrine also competitively inhibited the binding of nisoxetine[m]
to rat brain cortical slices, with a Ki = 4.5 μM; l-synephrine was
less potent (Ki = 8.2 μM). In experiments on the release of
[3H]-norepinephrine from rat brain cortical slices, however, the
l-isomer of synephrine was a more potent enhancer of the release (EC50
= 8.2 μM) than the d-isomer (EC50 = 12.3 μM). This enhanced release
by l-synephrine was blocked by nisoxetine.
Burgen and Iversen, examining the effect of a broad range of
phenethylamine-based drugs on [14C]-norepinephrine-uptake in the
isolated rat heart, observed that racemic synephrine[n] was a
relatively weak inhibitor (IC50 = 0.12 μM) of the uptake.
Another receptor-oriented study by Wikberg revealed that synephrine
(stereochemistry unspecified) was a more potent agonist at guinea pig
aorta α1 receptors (pD2 = 4.81) than at ileum α2 receptors (pD2 =
4.48), with a relative affinity ratio of α2/α1 = 0.10. Although
clearly indicating a selectivity of synephrine for α1 receptors, its
potency at this receptor sub-class is still relatively low, in
comparison with that of phenylephrine (pD2 at α1 = 6.32).
Brown and co-workers examined the effects of the individual
enantiomers of synephrine on α1 receptors in rat aorta, and on α2
receptors in rabbit saphenous vein. In the aorta preparation,
l-synephrine gave a pD2 = 5.38 (potency relative to norepinephrine =
1/1000), while d-synephrine had a pD2 = 3.50 (potency relative to
norepinephrine = 1/50000); in comparison, l-phenylephrine had pD2 =
7.50 (potency relative to norepinephrine ≃ 1/6). No antagonism of
norepinephrine was produced by concentrations of l-synephrine up to
10−6 M. In the rabbit saphenous assay, the pD2 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 pD2 =
5.45 (potency relative to norepinephrine ≃ 1/140). No antagonism of
norepinephrine was produced by concentrations of l-synephrine up to
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 −logKa = 3.75
in the aorta assay. In comparison, epinephrine had a potency of
−logKa = 5.70. There was no significant effect on the ileum at
synephrine concentrations up to about 2 × 10−4 M, indicating
selectivity for the α1 receptor, but relatively low potency.
In binding experiments with central adrenergic receptors, using a
preparation from rat cerebral cortex, l-synephrine had pIC50 = 3.35,
and d-synephrine had pIC50 = 2.42 in competition against [3H]-prazosin
(standard α1 ligand); against [3H]-yohimbine (standard α2 ligand),
l-synephrine showed a pIC50 = 5.01, and d-synephrine showed a pIC50 =
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
10−5–3 × 10−6 M. This constriction was found to be
competitively antagonized by prazosin (a standard α1 antagonist) and
ketanserin,[o] with prazosin being the more potent antagonist (pA2 =
9.38, vs pA2 = 8.23 for ketanserin).
Synephrine constrictions were
also antagonized by
BRL-15,572 Used here as a selective 5-HT1D
antagonist. , but not by
SB-216,641 (used here as a selective 5-HT1B
antagonist), or by propranolol (a common β antagonist).
In studies on guinea pig atria and trachea, Jordan and co-workers also
found that synephrine had negligible activity on β1 and β2
receptors, being about 40000x less potent than norepinephrine.
Experiments with cultured white fat cells from several animal species,
including human, by Carpéné and co-workers showed that racemic
synephrine produced lipolytic effects, but only at high concentrations
(0.1-1 mM). The potency, expressed in terms of pD2 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 pD2 = 8.29 and
norepinephrine had pD2 = 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
(IC50): bupranolol:[p] 0.11 μM; CGP-20,712A (β1 antagonist): 6.09
ICI-118,551 (β2 antagonist): 3.58 μM; SR-5923A (β3
antagonist): 17 μM.
The binding of racemic synephrine to cloned human adrenergic receptors
has been examined: Ma and co-workers found that synephrine bound to
α1A, α2A and α2C with low affinity (pKi = 4.11 for α1A; 4.44 for
α2A; 4.61 for α2C).
Synephrine behaved as a partial agonist at α1A
receptors, but as an antagonist at α2A and α2C sub-types.
Racemic synephrine has been shown to be an agonist of the TAAR1,
although its potency at the human
TAAR1 is relatively low (EC50 =
23700 nM; Emax = 81.2%).
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 (T1/2) of ~ 2 hours.
Studies of the metabolism of synephrine by monoamine oxidases derived
from rat brain mitochondria showed that synephrine was a substrate for
deamination by both
MAO-A and MAO-B, with Km = 250 μM and Vmax = 32.6
nM/mg protein/30 minutes; there was some evidence for preferential
deamination by MAO-A.
Effects in humans
This section needs more medical references for verification or relies
too heavily on primary sources. Please review the contents of the
section and add the appropriate references if you can. Unsourced or
poorly sourced material may be challenged and removed. (January 2014)
A number of studies of the effects of synephrine in humans, most of
them focusing on its cardio-vascular properties, have been performed
since its introduction as a synthetic drug around
1930. 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 mg)
of the drug produced an increase in systolic blood pressure and pulse
rate, without affecting the diastolic pressure. The blood pressure
increase reached a maximum (~25 mmHg) in 5 minutes following the
injection, then gradually returned to normal over the course of 1
hour. Doses of drug greater than 200 mg caused side-effects such
as heart palpitations, headache, sweating, and feelings of
apprehension. When given intravenously, doses of 25–50 mg
sufficed to produce a mean maximum increase in the blood pressure of
29 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 mg had
no effects on blood pressure or pulse rate. Oral doses of
500–1500 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.
The i.m. administration of 75–500 mg of synephrine did not
relieve acute asthma attacks, contradicting an earlier claim.
However, the topical application of 1–3% solutions of the drug to
the nasal mucosa of patients with sinusitis did produce a beneficial
constriction without local irritation.
A more recent study showed that the administration of synephrine by
continuous intravenous infusion, at the rate of 4 mg/minute,
significantly increased mean arterial and systolic pressure, but
diastolic pressure and heart rate were unaltered.; further details
of this investigation are summarized in a review by Fugh-Berman and
There are a number of studies, references to many of which may be
found in the review by Stohs and co-workers. 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
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 mg/kg; rat:
400 mg/kg; guinea pig: 400 mg/kg. "Lethal doses", given
s.c., were found to be: mouse: 400 mg/kg; rat: 500 mg/kg;
guinea pig: 500 mg/kg. Another study of this compound,[q]
administered i.v. in mice, gave an LD50 = 270 mg/kg.
The "subchronic toxicity" of synephrine was judged to be low in mice,
after administration of oral doses of 30 and 300 mg/kg over a
period of 28 days, in a recent study employing modern methodology
carried out by Arbo and co-workers. 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
Information about the safety and efficacy of synephrine used as a
single drug may be deduced from the foregoing review of the literature
in this Article. This information is, by and large, not contended.
However, 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, and much
has been written about such preparations in the medical literature and
on the Internet. Since
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,
further discussion is outside the scope of this article.
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)
Synephrine (racemic) is also more potent
than octopamine (racemic) at inducing light-emission in the firefly
Photinus species) light organ.
Synephrine exhibits similarly high
potency in stimulating adenylate cyclase activity and in decreasing
clotting time in lobster (Homarus americanus) hematocytes. Racemic
synephrine was found to increase cAMP in the abdominal epidermis of
the blood-sucking bug, Rhodnius prolixus. Rachinsky reported that
synephrine was equipotent with octopamine in stimulating JH (juvenile
hormone) release in the corpora allata of honey bee (Apis
mellifera), but Woodring and Hoffmann found that synephrine had
no effect on the synthesis of JH III, in in vitro preparations from
the cricket, Gryllus bimaculatus.
Synephrine does however not appear in the current FDA "Orange Book"
or the 2012 Physicians' Desk Reference.
^ About 1.0–0.02 mg/serving, based on a serving size of ~20g.
^ About 1.0–0.1 mg/serving.
^ Corresponding to roughly 1–15 mg/serving, assuming a 1-cup or 250
mL serving size.
^ For example, a recent review paper concerning the use of
synephrine-containing nutritional supplements states that: "There is
no consensus regarding which synephrine’s positional isomers are
present in CA [
Citrus aurantium]. The majority of authors state that
only p-synephrine can be found in CA fruits...although others claim
that m-synephrine is also present..." 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, 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.
^ ~ 5 x 10−4M.
^ ~ 2 x 10−3M.
^ ~ 3 × 10−4M.
^ Tail suspension and enforced swimming.
^ Ostensibly correlated to anti-depressant activity.
^ An adrenergic antagonist selective for α1 receptors.
^ Reversal of reserpine-induced hypothermia by a drug is a classical
test for potential anti-depressant properties.
^ A selective inhibitor of the norepinephrine transporter.
^ Referred to here as "oxedrine".
^ A drug often used as a selective 5-HT2A antagonist.
^ Used as a non-selective β-antagonist
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Major excitatory/inhibitory systems: Glutamate system: Agmatine
Aspartic acid (aspartate)
Glutamic acid (glutamate)
Serine; GABA system: GABA
Glycine system: α-Alanine
Taurine; GHB system: GHB
Biogenic amines: Monoamines: 6-OHM
Serotonin (5-HT); Trace amines: 3-Iodothyronamine
p-Tyramine; Others: Histamine
Neuropeptides: See here instead.
2-AGE (noladin ether)
Neurosteroids: See here instead.
Adenosine system: Adenosine
Cholinergic system: Acetylcholine
Carbon monoxide (CO)
Hydrogen sulfide (H2S)
Nitric oxide (NO); Candidates: Acetaldehyde
Carbonyl sulfide (COS)
Nitrous oxide (N2O)
Sulfur dioxide (SO2)
Adrenergic receptor modulators
Atypical antipsychotics (e.g., brexpiprazole, clozapine, olanzapine,
Ergolines (e.g., ergotamine, dihydroergotamine, lisuride, terguride)
Phenylpiperazine antidepressants (e.g., hydroxynefazodone, nefazodone,
Tetracyclic antidepressants (e.g., amoxapine, maprotiline, mianserin)
Tricyclic antidepressants (e.g., amitriptyline, clomipramine, doxepin,
Typical antipsychotics (e.g., chlorpromazine, fluphenazine, loxapine,
Atypical antipsychotics (e.g., asenapine, brexpiprazole, clozapine,
lurasidone, paliperidone, quetiapine, risperidone, zotepine)
Azapirones (e.g., buspirone, gepirone, ipsapirone, tandospirone)
Typical antipsychotics (e.g., chlorpromazine, fluphenazine, loxapine,
Human trace amine-associated receptor ligands
Classical monoamine neurotransmitters
† References for all endogenous human
TAAR1 ligands are provided at
List of trace amines
‡ References for synthetic
TAAR1 agonists can be found at
in the associated compound articles. For
TAAR5 agonists and
inverse agonists, see TAAR for references.
See also: Receptor/signaling modulators
Amphetamine (Dextroamphetamine, Levoamphetamine)
Fenfluramine (Dexfenfluramine, Levofenfluramine)
Methamphetamine (Dextromethamphetamine, Levomethamphetamine)
Selegiline (also D -Deprenyl)
(and close relatives)
D -DOPA (Dextrodopa)
L -DOPA (Levodopa)
L -DOPS (Droxidopa)
Lysergic acid amide
Lysergic acid 2-butyl amide
Lysergic acid 2,4-dimethylazetidide
Lysergic acid diethylamide