Synephrine
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. p-Synephrine 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 products, both of the "sweet" and "bitter" variety. The preparations used in traditional Chinese medicine, also known as Zhi Shi, are the immature and dried whole oranges from Citrus aurantium. 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 is still used as a sympathomimetic, mostly by injection for the treatment of emergencies such as shock, and rarely orally for the treatment of bronchial problems associated with asthma and hay-fever.
There is a difference between studies concerning synephrine as a single chemical entity, 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 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.
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. 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 Evodia and Zanthoxylum species, all plants of the family Rutaceae.Trace levels of synephrine have also been detected in the dried leaves of Pogostemon cablin. It is also found in certain cactus species of the genera Coryphantha and Dolichothele.
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, 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 synephrine ; 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 in those jams made from bitter oranges, and levels of 0.05 mg/g–0.006 mg/g of synephrine in jams made from sweet oranges.
Synephrine has been found in marmalade made from Citrus unshiu obtained in Japan, at a concentration of ~0.12 mg/g. Most of the orange marmalades made in the US are produced using "sweet" oranges, whereas "bitter" or Seville oranges are used for making the more traditional, bitterer marmalades in the United Kingdom.
A sample of commercial Japanese C. unshiu juice was found to contain ~0.36 mg/g synephrine, 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; 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 : ~85 mg/L; Nova tangerine : ~78 mg/L; clementine : ~115 mg/L; Meyer lemon ~3 mg/kg; Ugli tangelo ~47 mg/kg. No synephrine was detected in: Rio Red grapefruit ; Red-fleshed pummelo ; or Wekiwa tangelo.
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, 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 urine samples.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. Earlier, the same research group had reported a normal human blood plasma level of synephrine of 0.90–13.69 ng/mL.
Stereoisomers
Since synephrine exists as either of two enantiomers, which do not produce identical biological effects some researchers have examined the stereoisomeric 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, low levels of d-synephrine have been detected in juice and marmalade made from C. unshiu, and low levels 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 synephrine from a cactus of the genus Dolichothele, under conditions that would be unlikely to cause a significant amount of racemization.Biosynthesis
The biosynthesis of synephrine in Citrus species is believed to follow the pathway: tyrosine → tyramine → N-methyltyramine → 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 N-methyltransferase.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, bound up in the plant matrix, but could also be of synthetic origin, or a purified phytochemical. The concentration range found by Santana and co-workers in five different supplements purchased in the US was about 5–14 mg/g.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. 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." 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 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 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 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 administration.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.