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 (or formerly Sympatol and oxedrine [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, 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 (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.
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 (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 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 (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 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 (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 United Kingdom. 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; 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 research literature.
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