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Bitter Orange Peel and Synephrine

The following article is reprinted with permission from WholeFoods. Part 1 was published in the March 2004 issue of WholeFoods. Part 2 was published in the March 2005 issue. ©2005 American Botanical Council

It was not printed or reprinted in HerbalGram, but we offer it to our readers as a web-only exclusive.


Bitter Orange Peel and Synephrine: Part 1

Reprinted with permission from WholeFoods March 2004 issue (Part 2, published in March 2005 follows on this page). ©2005 American Botanical Council.

By Mark Blumenthal


The announcement in late December by the U.S. Food and Drug Administration (FDA) that it intends to issue regulations banning the sale of dietary supplements containing the controversial herb ephedra (Ephedra sinica) has stimulated a flurry of media articles about the sale, potential safety risks, and need for additional regulation of so-called ephedra-free dietary supplements and alternatives to ephedra supplements.*

Articles on this subject have appeared in The New York Times, USA Today, the Los Angeles Times, Time magazine, and many other publications and electronic news outlets (e.g., CNN, major television networks and local newscasts) about these alternative products. I have been interviewed by many of the above in the two weeks subsequent to the FDAs announcement of the proposed ban, as well as during the past year. One of the most frequently mentioned ingredients in all of these stories is bitter orange peel and its primary alkaloid, synephrine.

During this post-ephedra ban announcement period, bitter orange has become increasingly controversial. On January 20, FDA Commissioner Mark McClellan M.D., Ph.D. announced that FDA would be taking a stronger look at bitter orange to determine its safety (and presumably, its efficacy) as an ingredient in dietary supplements being marketed as ephedra-free products for weight loss (Weise 2004).

Over the past few years, especially since the highly publicized death of Baltimore Orioles pitcher Steve Bechler in February 2003a case that has been linked to Bechlers consumption of an ephedra supplementmany manufacturers have shifted to the so-called ephedra-free products for various reasons, most notably their desire to avoid the increasing adverse publicity associated with ephedra, and the other, because of the rising costs of product liability insurance coverage for ephedra.

The ephedra-free products contain a variety of herbs, some containing caffeine (e.g., green tea extract [Camelia sinensis], guarana [Paullinia cupana], cola nut [Cola acuminata, C. nitida], mate aka yerba mate [Ilex paraguariensis]), and cocoa extract [Theobroma cacao]), as well as the fruits of Garcinia cambogia and other ingredients. But its the bitter orange peel extract and its synephrine content that are getting most of the medias, and recently, the FDAs attention.

Botany and Distribution

Bitter orange also called Seville orange, is known botanically as Citrus x aurantium, L. of the family Rutaceae, and sometimes by its taxonomic synonyms, C. aurantium L. subsp. aurantium and C. aurantium subsp. amara (L.) Engler. Bitter orange is known by many local common names in countries around the world where it is used for food, fragrance and medicinal purposes. The peel of the immature fruit is known as Chi shi or zhi shi in Traditional Chinese Medicine (TCM). According to one authoritative source, zhi shi is sometimes derived from the immature fruit of C. sinensis Osbeck collected from May to June (Tang and Eisenbrand 1992). The peel of the mature fruit, also used in TCM, is called zhi qiao, although some sources confuse these two materials.

Bitter orange most likely originated in Southeast Asia and was initially propagated in India and Persia. In the 10th and 11th centuries Arab traders spread it around the Mediterranean countries: Syria, Palestine, North Africa, Sicily, Sardinia, the south coast of France, (i.e., Provence), and Spain. After the discovery of the New World it was introduced into the Caribbean (Peyron 2002). It is presently commercially cultivated in southern Europe and other subtropical areas, particularly Spain, Portugal, Israel, and the various islands of the Caribbean (Bisset and Wichtl 1994).

Modern Food, Fragrance Uses

The bitter orange tree is the source of numerous commercial products used in the fragrance and food industries. Neroli oil is steam distilled from the flowers. Petitgrain oil is made by steam distillation from the buds and leaves of bitter orange; the term petitgrain was first used for oil made from the small green fruits (orangettes) (Peyron 2002).

In the fragrance industry, the products from the bitter orange tree include neroli oil, bitter orange flower absolute (an absolute is a concentrated flower oil used in the fragrance industry), bitter orange flower water absolute, bitter orange petitgrain oil (bitter orange leaf oil), bitter orange leaf water absolute, bitter orange petitgrain absolute and other petitgrain oils (Buccelato 2002).

In the food industry, bitter orange oil, which is usually expressed from the fresh peels, is widely used as a flavoring agent. Bitter orange oil is used as flavorings for beverages, particularly liqueurs and to intensify the orange character of soft drinks (Colombo et al. 2002).

Bitter orange fruits, peels, and the oil from peel are all used to make orange marmalade. Most orange marmalades produced in the United States are made with the fruits and peels of the sweet orange (C. sinensis), while most of the original-style, more bitter-tasting marmalades made with true bitter orange (Seville orange) are made in the United Kingdom. Thus, as I have repeatedly told the media, bitter orange is not an exotic ingredient. According to an FDA guidance document, There is no formal standard of identity for marmalades. However, to avoid misbranding, a product labeled sweet orange marmalade should be prepared by mixing at least 30 pounds of fruit (peel and juice) to each 70 pounds sweetening ingredients. Sour or bitter (Seville) orange marmalade, lemon marmalade, and lime marmalade should be prepared by mixing at least 25 pounds of fruit (peel and juice) to each 75 pounds of sweetening ingredient. The amount of peel should not be in excess of the amounts normally associated with fruit. [emphasis added] The product should be concentrated to not less than 65% soluble solids. (FDA guidance 2004). A study published in 1995 showed that a sample of orange marmalade made from C. unshiu contained a total of 12.46 mg synephrine (0.36 d-synephrine + 12.1 mg l-synephrine,) based on mg/100 grams of marmalade, according to high-performance liquid chromatography (HPLC) (Kusu et al. 1995). These calculations suggest synephrine at 0.01% in the marmalade, or about 12 mg in 3.5 ounces, an extremely low level of synephrine.

Bitter orange materials are not as plentiful in the market as sweet orange. In contrast to the production of sweet orange oil, the production of bitter orange is barely sufficient to satisfy commercial demands. (McHale 2002). Because its production is more limited, the bitter orange oil is more expensive than sweet orange oil and is thus subject to potential adulteration with cheaper materials (McHale 2002).

The peels of both bitter orange and sweet orange are used in the formulation of herbal teas due to the peels flavor profiles, their digestive and carminative effects, and for the production of stomachic, carminative, and laxative products (Leung, Foster 1996).

Use of bitter orange Peel in TCM

The two Chinese traditional medicines, zhi qiao and zhi shi, are obtained from the bitter orange fruit, the former from the more matured orange peel, collected in July (though still green) and the latter from the immature orange (collected May through June, not fully developed).CAThey both are used to treat what westerners term indigestion, though they are more generally used to treat what is referred to in TCM as qi stagnationCA(Dharmananda S. Personal communication to M. Blumenthal, Jan. 31, 2004).

In TCM, zhi shi is used for the following indications, as described within the language of TCM: To break qi [chi, i.e., life force energy] and reduce food accumulation; to resolve phlegm and eliminate distention and fullness. (Dharmananda 2003). The indications for which it is used include food retention, constipation with abdominal pain, diarrhea and dysentery with tenesmus [the urgent feeling to urinate or defecate, without success]; distention and full sensation in the chest and epigastrium [the upper middle abdominal area] caused by phlegm-turbidity blocking the circulation of qi. (Dharmananda 2003). The dosage ranges 3-10 grams of the dried fruit in decoctions per day. TCM precautions include using caution when using in patients with spleen and stomach deficiency or during pregnancy (Dharmananda 2003).**

Also, dried bitter orange fruit, and, less commonly, the peel are used in treating prolapse of the uterus and anus, diarrhea, and blood in the feces (Leung, Foster 1996). It has also been used as an expectorant and digestant (Tang, Eisenbrand, 1992).

Eclectic and Modern Medicinal Uses

Bitter orange was used by the Eclectic physicians of the late 19th and early 20th centuries. According to the entry for bitter orange in Kings American Dispensatory, a reference of significant regard by herbalists and naturopaths who explore the empirical use of herbs by the Eclectic medical movement, bitter orange peel was used as a digestive tonic and as a flavoring agent for other medicines.

Orange peel is aromatic and slightly tonic, but is seldom used except to cover the taste of disagreeable medicines or to lessen their tendency to nausea, and for these purposes it is frequently added to bitter tinctures, infusions, etc., as quassia, Peruvian bark, etc.; though care should be taken not to subject it to long boiling on account of its oil, which will thus be dissipated. For tonic use, the rind of the Seville orange is preferred; its dose in substance is from 30 to 60 grains 3 times a day. (Felter and Lloyd, 1898).

In modern European herbal medicine, bitter orange peel is for dyspepsia and related conditions. According to the package insert from the German Standard License it is used as a supportive measure in treating stomach complaints, e.g., insufficient formation of gastric juice, and to stimulate the appetite (Bisset, Wichtl 1994). The German Commission E recognizes the medicinal value of bitter orange peel for loss of appetite and dyspeptic complaints; daily dosages are given in ranges of 4-6 grams for the dried peel, 2-3 grams for the tincture, and 1-2 grams for the extract (Blumenthal et al. 1998).


One of the chemicals of primary interest in bitter orange peel in todays market is synephrine. Synephrine was initially created synthetically as a sympathomimetic drug (see below), and was later discovered and isolated from the leaves and fruits of various species of Citrus, particularly C. aurantium (Tang, Eisenbrand 1992). Synephrine has also been reportedly found in the fruit and peel of some varieties of tangerine (e.g., C. reticulata, aka chenpi in TCM; unripe fruit peel = qingpi), and even possibly in sweet orange (C. sinensis). In general, the levels vary greatly, from 0.1% to 2.0%. Synephrine is created in the fruits growth in a chemical pathway involving tyramine and N-methyltyramine (Tang, Eisenbrand 1992).

Synephrine is an alkaloid (a pharmacologically active class of nitrogen-containing chemical compounds). Its chemical structure is similar to ephedrine, the primary active alkaloid in ephedra, aka ma-huang. There are only two chemical differences between ephedrine and synephrine: in synephrine one of the ring carbons is hydroxylated (a hydroxyl group { OH}  replaces a hydrogen atom { H} ), and a side chain methyl group (CH3; Me) is replaced by hydrogen. Synephrine is found mainly in the medicinal products derived from citrus, although it has been reported in small amounts in the Chinese evodia fruit (Evodia rutaecarpa), wu zhu yu in Chinese. Synephrine is also found in a few other plants, including the rubber tree (Wheat and Stewart 1970) (see below).

Synephrine has been incorrectly characterized in some of the published literature. The type of synephrine found in bitter orange peel is p-synephrine (para-synephrine), not m-synephrine, which is what is said to be in bitter orange by various authors. M-synephrine (meta-synephrine) is also called phenylephrine (aka neosynephrine). A comprehensive review of the presence and distribution of synephrine and chemically similar compounds (tyrmaine, n-methyltyramine, hordenine, octopamine) in higher plants was published in 1970, showing that with a few exceptions of non-food plants, synephrine is found mainly in the genus Citrus (Wheaton, Stewart 1970).

Synephrine and related alkaloids appear to be present in slightly higher quantities in the unripe fruit than in the ripe fruit. The amount of synephrine in blue citrus (qing pi), an immature citrus fruit, is 0.26% and in citrus (chen pi), a mature citrus fruit, the level is 0.22%. In an evaluation of four different dried citrus fruits used in Japanese herbal medicine, the synephrine content did not show much variation. Some citrus materials that have been assayed in China have a higher synephrine content; in one study, synephrine levels in citrus fruits and peels ranged from as little 0.1% to a very high 2.0%, while most reports place the level at about 0.25%. One Japanese study found that the level of synephrine was found to decrease corresponding with an increase in the diameter of the dried immature fruits of the variety known in Japan as kijitsu (C. unshiu), which was found to have higher synephrine levels than C. aurantium or C. hassaku (Hosoda et al., 1990).

Because synephrine is found in the fruits of various species of Citrus, it is also inevitably found in the juices of numerous popular citrus varieties, making the presence of synephrine more widespread in the conventional food supply than many people probably recognize. The synephrine levels of various citrus juices is shown in Table 2.

Table 1: Synephrine Levels in Bitter Orange Materials
Materialmg% (mg/100 g)
Fresh fruit270 mg0.020
Dried fruit3800.352
Dried extract30003.003 3.079
Products250-25000.250 0.989
Source: Pellati et al. 2002


Table 2 Synephrine Levels in Citrus Juices
Fruit & VarietySynephrine level***
Cleopatra mandarin280
***Values are stated in mg/liter of juice for single juice sample (in most cases). (from Wheaton, Stewart 1965)


Numerous dietary supplements currently on the market contain varying levels of bitter orange peel extract, at various levels of standardization to synephrine. As can be expected, there are also various other herbal and other ingredients included in these formulations.

Regarding synephrine levels in these supplements, the synephrine levels also vary, both in the amount in each dosage form (capsule or tablet) and/or in the amount of synephrine a consumer would ingest on a daily basis, based on the products directions for use.

The following dietary supplement products were chosen at random from a Google search of the Internet: Cytodyne Xenadrine EFX, one of the leading products in the market, contains a variety of nutritional ingredients, plus the Proprietary Thermodyne Complex, totaling 1,415 mg per tablet. This complex contains tyrosine, standardized extracts of green tea, cocoa, yerba mate, ginger root, bitter orange (standardized to synephrine and other alkaloids and amines), plus other ingredients ( accessed Feb. 2, 2002). There is no information on the website that allows a determination of the bitter orange peel extract levels nor the synephrine and other amine levels in each dose. Directions suggest two capsules before morning exercise, and two in the afternoon with 8 ounces of water, not to exceed four capsules per day (written in upper case type). There is also an extensive warning given, including the suggestion that persons under 150 pounds may want to use half the recommended levels for the first week.

MetaSlim contains 150mg bitter orange extract (concentrated to 6:1, containing 6% synephrine). The recommended dose is 1-2 tablets in the morning, providing a one-time daily dose of 24 mg synephrine. (, accessed Jan. 28, 2002)

Trim Fit with Advantra Z Tonalin (produced by by Quest of Canada): One daily dose (six capsules) contains Advantra-ZT (a proprietary bitter orange peel extract, standardized to 4% synephrine. The total weight of bitter orange peel in six capsules is 1,050 mg (= 42mg synephrine). The product also contains green tea extract, Tonalin (a source of conjugated linoleic acid, CLA), St. Johns wort (Hypericum perforatum), and other ingredients. (, accessed Jan. 28, 2002)

There has been confusion in the popular literature about the purported presence of another alkaloid in bitter orange peel, octopamine. An issue of the Cornell Department of Nutrition Newsletter stated that octopamine, in invertebrates, is used as a pesticide and, in humans, is known as a false neurotransmitter because it alters the normal function of the brain and is believed to stimulate the production of growth hormone. It also acknowledges studies supporting the belief that octopamine could be considered as an endogenous selective beta-3 adrenoceptor agonist and could be useful in weight loss. It may also be useful in glucose transport. Presently, says the newsletter, it is being marketed as a weight-loss product having thermogenic properties and as an appetite suppressant. The Cornell publication warns consumers about the potential additive effect of the octopamine and synephrine (Anon, Cornell newsletter 1999). However, various analytical studies on bitter orange peel, particularly on the immature peel, like the Chinese zhi shi material, has produced no evidence that octopamine is present in any appreciable levels (Pellati 2002; Wheaton, Stewart 1970).

Look for Part 2

Limitations of space being what they are, we are going to break off this discussion at this point and pick it up in a forthcoming Part 2. At that time, we will consider synephrines pharmacology, clinical trials on bitter orange peel extracts, safety data for bitter orange and synephrine, and regulatory issues, and we will present a list of references.


Mark Blumenthal is the founder and executive director of the American Botanical Council (ABC) in Austin, TX, a non-profit organization, and is editor of its journal HerbalGram. He also served as lead editor of two books in English on the German Commission E monographs, one of the worlds most comprehensive considerations of herbal medicine. His most recent booklength effort is The ABC Clinical Guide to Herbs, in which he and six co-author/editors present extensive information on 29 of the most popular herbs sold in the U.S. market today. A frequent lecturer and talk-show guest, Blumenthal has been in the natural food and herb industries for over three decades, functioning as a wholesaler, manufacturer, journalist, consultant and educator.


Authors Notes

* At press time, the FDA has not yet published its final rule regarding how and when the ban would go into effect.

** It should be noted that spleen deficiency does not refer to the organ known as the spleen in western anatomy. In TCM the spleen and stomach represent the digestive system. The spleen plays an essential role involving the transportation and transformation of nutrients, control of blood flow and responsibility for anxiety. The spleen also is related to the musclesC9. When patients have chronic fatigue and digestive disorders, they are often diagnosed by [TCM]as spleen deficient. Generally, this means that the spleens role is dysfunctional. Because of spleen deficiencies, nutrients cannot be distributed properly for the bodys needs. The body lacks energy, so fatigue occurs. Spleen deficiency also causes digestive dysfunction. Typical symptoms are poor appetite, bloating of the abdomen or chronic diarrhea. (Ren 2001).