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.

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 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 mg/g;[10] 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.

[11] 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.

[13] Synephrine has been found in marmalade made from Citrus unshiu (Satsuma mandarin)[14] obtained in Japan, at a concentration of ~0.12 mg/g (or about 2.4 mg/20g serving).

[14][19] Numerous additional comparable analyses of the synephrine content of Citrus fruits and products derived from them may be found in the research literature.

[40][41] 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).

"[42][43] 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.

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.[48] 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.

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.

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.

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.

Extension of the synephrine N-methyl substituent by one methylene unit to an N-ethyl gives the hypotensive experimental drug "Sterling #573"/"Aethyl-Sympatol".

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.

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.

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 epinephrine.

[63] 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.

[41] 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.

[41] Experiments on strips of rabbit duodenum showed that l-synephrine caused a modest reduction in contractions at a concentration of 1:17000,[g] but that the effects of the d- and d,l- forms were much weaker.

[43] 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.

[65] These researchers observed that oral doses of 0.3 – 10 mg/kg of racemic synephrine were effective in shortening the duration of immobility[i] produced in the assays, but did not cause any changes in spontaneous motor activity in separate tests.

[66] 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[m] was a relatively weak inhibitor (IC50 = 0.12 μM) of the uptake.

[69] 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,[n] with prazosin being the more potent antagonist (pA2 = 9.38, vs pA2 = 8.23 for ketanserin).

[71] 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.

[72] 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 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.

[84] 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.

[85] There are a number of studies, references to many of which may be found in the review by Stohs and co-workers[86] dealing with the effects produced by dietary supplements and herbal medications that contain synephrine as only one of many different chemical ingredients.

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.

[98] Synephrine exhibits similarly high potency in stimulating adenylate cyclase activity and in decreasing clotting time in lobster (Homarus americanus) hematocytes.