Issue: 66 Page: 0
Bitter Orange Peel and Synephrine
HerbalGram. 2005; 66:0 American Botanical Council
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 FDA’s 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 2003—a
case that has been linked to Bechler’s consumption of an ephedra
supplement—many 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 it’s the bitter orange
peel extract and its synephrine content that are getting most of the media’s,
and recently, the FDA’s 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 stagnation”CA(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 King’s
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).
Chemistry
One of the chemicals of primary interest in bitter orange peel in
today’s 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 fruit’s 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 |
Material |
mg |
% (mg/100 g) |
Fresh fruit |
270 mg |
0.020 |
Dried fruit |
380 |
0.352 |
Dried extract |
3000 |
3.003 – 3.079 |
Products |
250-2500 |
0.250 – 0.989 |
Source: Pellati et al. 2002 |
Table 2 Synephrine Levels in Citrus Juices |
Fruit & Variety |
Synephrine level*** |
Orange |
Hamlin |
22 |
Navel |
15 |
Pineapple |
27 |
Valencia |
19 |
Tangerine |
Dancy |
125 |
Lemon |
Meyer |
2 |
Cleopatra mandarin |
280 |
***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 (www.cytodyne.com) 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. (www.zooscape.com, 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. John’s wort (Hypericum
perforatum), and other ingredients. (www.zooscape.com, 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 synephrine’s 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 world’s 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.
Author’s 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
spleen’s role is dysfunctional. Because of spleen deficiencies, nutrients
cannot be distributed properly for the body’s 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).
Bitter Orange Peel and
Synephrine: Part
2
By Mark Blumenthal
Reprinted with permission from WholeFoods 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.
This is the second part of a comprehensive article on bitter
orange, the first part having been published in WholeFoods in March 2004.
The article was originally planned and much of it was written in late 2003 and
early 2004, when the FDA had just announced its intention to ban the then increasingly
controversial herb ephedra (Ephedra sinica) from all dietary supplements,
said ban going into effect on April 12, 2004. For several years prior to the
ban, many dietary supplement manufacturers had started the trend toward “ephedra-free” supplements
for weight loss and/or athletic performance, many of these supplements containing
bitter orange extract.
When I originally wrote the initial drafts of this article
for WholeFoods, in order to include many
of the details I thought were important to understanding the various aspects
of bitter orange and its current role in the dietary supplement industry, I wrote
an article that became too long for the magazine to publish in one issue. Hence
the first half, dealing mainly with the botany, geographical distribution, chemistry,
food use and other aspects of bitter orange was published last year. I intended
to revise and complete the second half, dealing with pharmacology, clinical trials
and safety—and publish it shortly afterward. However, other editorial,
organizational and personal priorities became paramount for me, and the completion
of part 2 was set aside. Now, after a full year, we are happy to present the
second half.
Confusion on Adverse Events and Bitter Orange
During the intervening year, there has been some interesting
controversy surrounding bitter orange. However, the controversy is somewhat different
from that which surrounded and eventually created the demise of ephedra. Whereas
ephedra went down after various reports of deaths of several highprofile athletes
and after years of concern about reports of serious adverse events associated
with its use, the pharmacovigilance field and the media have been relatively
quiet about bitter orange, at least compared to ephedra. To my knowledge, there
have been few confirmed, reliable adverse event reports implicating bitter orange
and/or bitter orange-containing dietary supplements with any serious injury
or death. Not that there haven’t been some stories about some
such reports. If this sounds like a contradiction,
I’ll explain. In April 2004 The New York Times published a story (Hurley, 2004) about bitter orange
that stated that the reporter had received from FDA some data saying that there
were 85 adverse reactions (adverse event reports, AERs) and seven deaths associated
with bitter orange. This was big news to many people in the herb industry as
well as people in the research and academic communities who were not familiar
with such reports. The American Herbal Products Association’s president,
Michael McGuffin, published a deconstruction of these putative AERs, finding
that many were either duplicates in the FDA’s AER database or were associated
with products containing both bitter orange and ephedra,
and thus most of these reports cannot be used to help evaluate the relative safety
or risks of bitter orange (McGuffin, 2004). In fact, in McGuffin’s analysis,
he finds only one serious AER that can be clearly attributable to a supplement
containing bitter orange.
The American Association of Poison Control Centers’ Toxic
Exposure Surveillance System [TESS] report for 2003 contains about 40 incidents
related to bitter orange as a single ingredient and as a multi-ingredient supplement.
However, these 40 incidents cannot be interpreted as all related to adverse events,
either minor or serious. Besides, the TESS system has been shown to be unreliable
insofar as determining which reports are actually merely consumer inquiries or
incident reports as compared to actual reports of minor or serious adverse reactions
[Kingston and Blumenthal, 2003].
Consequently, some of the reports associated with bitter orange
in the TESS database cannot be viewed a priori as “adverse.”
In Canada one publication has suggested some adverse events
associated with bitter orange preparations. Writing in a newsletter published
by Health Canada on adverse event reports, Scott Jordan, Ph.D. and colleagues
state that between January 1, 1998 and February 28, 2004 Health Canada received
16 reports “in which products containing bitter orange or synephrine
were suspected of being associated with cardiovascular ARs [adverse events],
including tachycardia [rapid heart beat], cardiac arrest, ventricular fibrillation,
transient collapse and blackout.” (Jordan et al,
2004). All cases were considered serious. However, a review of these cases indicates
that in eight instances the products involved also contained both Ephedra/ephedrine
and caffeine—a
combination that has been widely discussed for its potential risks. Only one
case involved a suspect product containing bitter orange but no caffeine or Ephedra/ephedrine.
In seven cases the suspect product also contained caffeine. Two of the 16 patients
died, both of whom had taken products containing Ephedra/ephedrine and
caffeine in addition to bitter orange. The authors state that evaluation of these
reports is challenging because of many factors such as the lack of information
on the ingested dose of synephrine, the contributory effects of other (multiple) ingredients
such as Ephedra and caffeine, and the ambiguity of the reported information.
A Serious Adverse Event Case
A recent report of a myocardial infarction (MI or heart attack)
in a 55-year-old woman will no doubt become increasingly cited as a serious AER
warranting the possible closer restriction of bitter orange in dietary supplements
(DS) (Nykamp et al, 2004). The woman reportedly
had a history of smoking tobacco, was reportedly inactive (did not exercise)
and had a heart murmur—any or all of which could have contributed to her MI.
For one year, she had been using a product called “Edita’s Skinny
Pill” containing 300 mg bitter orange (company materials did not specify
if this was powdered herb or an extract). The authors of the report conclude
that, “the acute lateral-wall MI was possibly associated with bitter orange.” The
authors conjecture that the patient’s use of the bitter orange DS may have
precipitated an MI based on her underlying but previously undetected cardiovascular
disease; they employed the Naranjo probability scale to confirm the possible
association with bitter orange. In February, 2004, Edita Kaye, founder of The
Fountain of Youth Group in Ponte Vedra, FL, agreed to stop marketing “Skinny” dietary
supplements without “reliable scientific evidence” that they work,
under a proposed settlement with the Federal Trade Commission, after the FTC
accused her of false advertising and deceptive trade practices in a lawsuit filed
in January. Kaye, a medical journalist, had been under investigation after unveiling “Skinny
Pills for Kids” in 2002 (Early, 2004).
Reviews of Bitter Orange
A few months after the New York Times article appeared, a review paper (Fugh-Berman and Myers,
2004) was published in a scientific journal. After reviewing the clinical trials
on bitter orange, the authors concluded that from an efficacy perspective, “the
only published trial [referring to Colker et al., 1999] of C. aurantium- containing weight-loss product [a combination product]
found that the product was not superior to placebo for weight loss. There is
no evidence that synephrine and octopamine in levels that would be found in weight-loss
products would have any lipolytic effect on human adipocytes.” (Fugh- Berman
and Myers, 2004). With respect to safety, the authors state, “C.
aurantium would be expected [emphasis added to denote that this is still somewhat
speculative] to have sympathomimetic effects, but C. aurantium extracts have not been associated with adverse effects
to date.”
The authors properly point out that no trials have been conducted
on bitter orange alone; they are all based on combination products, in which
caffeine-containing herbs are usually included. The authors warn consumers to
avoid taking bitter orange products until bitter orange’s safety has been
adequately established by more research. However, the only adverse cardiovascular
effects related to bitter orange and synephrine they could find were based on animal
and human research in which bitter orange or synephrine were injected not ingested. Big difference! They also write, “There is
some evidence that C. aurantium extracts
have different effects than pure synephrine, but these differences must be explored
in appropriately designed studies. It is not unusual for crude herb extracts
to have very different effects than isolated constituents. However, data available
to date are insufficient to support safety claims of C. aurantium extracts.” (Fugh-Berman
and Myers, 2004)
During 2004 there have been other scientific reviews of bitter
orange. The most ambitious has been an 87-page report by the National Toxicology
Program (NTP) of the National Institute of Environmental Health Sciences (NIEHS),
an institute of the National Institutes of Health (NIH) (NTP, 2004). NTP contracted
for the report because bitter orange was nominated by a “private individual” (unnamed)
for a toxicological review due to its increased popularity in “ephedra-free” dietary
supplements “and limited data to demonstrate its safety for this use.” (NTP,
2004)
This report is probably the most comprehensive compilation
of data on bitter orange conducted to date, based on 18 pages of references (the
American Botanical Council’s Herbal Medicine: Expanded Commission E
Monographs [Blumenthal, 2000] is cited eight
times). Interestingly, and consistent with this author’s findings, the
NTP report states that the only “authoritative” review of bitter
orange is the brief therapeutic monograph published by the German Commission
E, intended for use as a package insert for bitter orange preparations sold as
nonprescription medications for loss of appetite and dyspeptic complaints in
Germany (Blumenthal et al., 1998).
The NTP report covers the following subject areas: Chemistry,
Production Processes, Production and Import Volumes (not supplied, noted as “no
data available”), Uses, Environmental Occurrence and Persistence, Human
Exposure, Regulatory Status, Toxicological Data (includes many subheadings),
and Structure-Activity Relationships.
The NTP report on bitter orange, synephrine, and octopamine is a comprehensive
literature review intended as a background document to be presented to government
officials who will eventually determine whether a material (an herbal ingredient
or an isolated chemical in the food supply, for example) that has been nominated
for such review should be evaluated for its safety. The NTP review provides information
on what previous studies have been published and what endpoints should be studied
in future reviews and new research. The report is not intended to be a policy
document but merely to help establish priorities in future research. The NTP
report has not been made available to the public, nor has it resulted in any
publicly available recommendations to the FDA or other relevant government agencies,
at least insofar as this writer has been able to determine. (In January 2005
this writer attempted to clarify the current status of this document but have
received no response by the time this article was completed.) (Personal communication
to William Eastin, Toxicology Operations Branch at the NIEHS/NTP, January 22,
2005).
The Executive Summary of the NTP report contains the following
language in a section called “Human Data”: “Many studies
have been conducted regarding the effects of products whose ingredients include
both ephedrine and bitter orange. Some report no adverse effects, while others
report that the use of bitter orange with stimulants such as ephedra causes cardiotoxicity.
When used in products for weight loss, which may be combined with ephedra, adverse
effects included sensitivity to light, an increase in blood pressure, and heightened
anxiousness. Similarly, studies of supplements containing synephrine plus caffeine
are also controversial. The combination of synephrine and caffeine (in other
herbs such as guarana and maté) has been reported to have the same potential
in inducing cardiac arrhythmias, hypertension, heart attacks, and strokes as
that of ephedra and caffeine.” (NTP, 2004).
The Abstract of the NTP report states: “Extracts
used in many dietary supplements and herbal weight-loss formulas as an alternative
to ephedra have concentrations of the sympathomimetic alkaloid synephrine that
are often much higher than the synephrine concentrations reported for traditional
extracts of the dried fruit or peel. Concentrations of octopamine in extracts
are less than those reported for synephrine. Weight-loss formulas usually contain
100-200 mg bitter orange extract, which provides 10-40 mg synephrine per dose.” (NTP,
2004)
The Structure-Activity Relationships section “discusses
the physiological effects, including toxicity, of certain structural analogs
of synephrine and octopamine and briefly reviews studies that compare the cardiovascular
effects of synephrine and/or octopamine with those of other biogenic amines.
The structural analogs include the catecholamines; several bronchodilators including
ephedrine and terbutyline; nasal decongestants including phenylephrine, phenylpropanolamine,
and pseudoephedrine; and appetite suppressants such as amphetamines.” (NTP,
2004) Many of these data are derived from injected (intravenous [i.v] or intraperitoneal
[i.p.]) administration to animals and humans of various isomers of synephrine
and also analogs (other chemical compounds with a structure similar to synephrine).
The relationship of the activities of these other compounds and various modes
of administration may be of questionable relevance to orally consumed synephrine
in bitter orange preparations, but they are included in this report as part of
the totality of dataset.
It bears emphasis that the NTP report makes no conclusions
regarding the proposed toxicity of bitter orange and/or synephrine with respect
to any recommendations for any regulatory action.
Of considerable importance in the NTP report is the statement
that it focuses on the para isomers
of synephrine and octopamine found in bitter orange peel, i.e., p-synephrine
and p-octopamine, “the most frequently
noted biogenic amines found in the peel.” Unless otherwise stated, the
report’s use of the terms “octopamine” and “synephrine” designates
the para isomers; “in most cases, when authors [of studies cited in the
text] did not specify the form, the para form was meant.” [NTP, 2004] This
is crucial to the understanding of the data cited in the report, as the m and
other isomers of synephrine are known to have different pharmacological activity
than the pisomer.
Pharmacology
As noted in the Chemistry section of Part 1 of this article
(see WholeFoods, March 2004), synephrine
is chemically similar to ephedrine. This chemical similarity has
led some observers to presume that the pharmacological activity of synephrine is identical
to ephedrine—a conclusion that does not appear to be fully supported by
the available literature.
Because of the chemical similarity with ephedrine, there has
been confusion as to whether synephrine affects the central nervous system (CNS). According
to the NTP report (2004), it does not affect the CNS (“Pharmacologically,
synephrine is similar to ephedrine but does not have its central nervous system
(CNS) effects.”). Both ephedrine and synephrine affect alpha-adrenergic receptors
and, to a lesser extent, beta-adrenergic receptors. Other alkaloids, e.g.,
octopamine, in bitter orange have similar actions. Both ephedrine and synephrine (only
when injected, according to the available research) can raise blood pressure
and have other effects on the cardiac function which, when under professional
care and administration of proper dosages, may benefit selected patients.
But the action of synephrine is dependent on several important factors:
aside from dosage, the isomeric form of the synephrine is critical, as is the mode of administration. Different types or isomers of synephrine can have varying
pharmacological effects, and the various modes of administration (e.g., intravenous
[i.v.], the route often used in pharmacological testing on animals, versus oral)
can produce markedly differing actions on cardiovascular parameters than oral
administration, which, obviously, is the route used in human ingestion of dietary
supplements.
Synephrine is considered a non-selective beta-3 agonist. It
is a generally accepted theory of pharmacology that beta-3 agonists affect body
weight and fat mass (Preuss et al., 2002),
activating lipolysis, the breaking down of fats (Carpene et al., 1999). In a study on animals and humans, synephrine was found
to be “partially active” in humans (Carpene et al., 1999). Normally, according to one source with considerable
experience in the area of the pharmacology of synephrine, synephrine is not well-absorbed
in the gastrointestinal tract (Jones, 1999). As an isolated pure drug, synephrine is often administered via
injection; thus, the pharmacological effects observed for synephrine when injected are
not generally applicable to its effects when it is consumed as part of a bitter
orange extract-containing dietary supplement. This issue of mode of administration
and of the relatively poor oral absorption of synephrine is obviously significant, particularly
for dietary supplements, which, by legal definition are consumed orally. Unfortunately,
published reports have sometimes confused these factors, thereby producing conflicting
results and possibly misleading both professional and public understanding of
the relative safety of synephrine.
Synephrine has also been reported to be a sympathomimetic alpha1-adrenoceptor
agonist, i.e., like ephedra alkaloids,
it can stimulate the sympathetic nervous system, producing what has been generally
referred to as a “fight or flight” response. However, synephrine reportedly
enters into and is less active on the CNS than ephedrine (Jones, 1999). Therefore,
synephrine is believed to have fewer adverse effects on the beta 1 and 2 receptors than
ephedrine (Jones, 1999; Kalman, 1999). According to literature discussing the
potential benefits of bitter orange in weight-loss formulations, “The theory
behind the use of Citrus aurantium is that it will augment thermogenesis
[the production of body heat through increased metabolism and the resultant loss
of calories and weight] and calorie consumption, but at the same time, produce
less cardiovascular perturbation than ephedrine” (Arch and Ainsworth, 1983).
However, this older paper has been questioned. More recent studies suggest that
octopamine works fairly well in stimulating lipolysis in rat fat in vitro,
but not very well in human fat in vitro (Carpene et
al., 1999).
Despite the promise of this hypothesis, there apparently are
not any well-accepted drugs for inducing weight loss that use this proposed mechanism.
A potential concern about bitter orange is whether it will
interact with a variety of prescription drugs. Bitter orange (like grapefruit
and grapefruit juice) contains a compound that inhibits an enzyme CYP3A4, part
of the cytochrome P450 digestive enzyme system in the small intestine; this enzyme
can alter the metabolism of drugs, in this case by inhibiting the production
of the metabolizing enzymes, thereby potentially boosting the drugs’ levels
in the blood and thus their activity. Synephrine is a substrate for monoamine
oxidase (MAO) A and B, according to research on rat brain mitochondria (Suzuki et
al., 1979). This can be considered a rationale
for a warning on the potential interaction between synephrine and monoamine oxidase-inhibiting
drugs (MAOIs) which can cause an increase in synephrine’s potential stimulant activity,
as is the case with ephedra supplements and OTC drugs containing ephedra alkaloids
(ephedrine and pseudoephedrine) and foods containing tyramine.
A form of synephrine (m-synephrine)
is sold as a drug in Europe (neosynephrine; Sympatol). It is officially listed
in the Nordic and the German pharmacopeias and is mainly used for treatment of
asthma and hypotension. Clinical testing has demonstrated that when given by
an i.v. infusion to healthy volunteers at a rate of 4 mg/minute, synephrine increased
systolic and mean arterial blood pressure, increased cardiac index, and decreased
peripheral vascular resistance, but did not affect diastolic pressure and heart
rate (Hofstetter et al., 1985).
This suggests that synephrine can be considered a stimulant of cardiac performance, usually when
administered via injection. However, these effects are based on the isolated synephrine and are not reported
in the literature as actions for the crude bitter orange peel or immature fruit
extracts, its decoction, or other traditional preparations of citrus materials
used as orally administered medicinal preparations in traditional Chinese medicine
(TCM). Some research shows that these effects are seen as properties of zhi-shih aqueous
extract or isolated synephrine. These materials have been used in China to treat shock
(Chang and But 1986) along with isolated ginsenoside saponins from Asian ginseng
(Panax ginseng) (Dharmananda 2003),
again, usually via injection.
In China, in cases of shock, i.v. synephrine and Nmethyltyramine are
administered, depending on the severity of the shock, at doses of 20-60 mg each,
diluted in normal saline or glucose solution (Chang & But 1987). Intravenously
administered synephrine has a biological half-life (i.e., the time it takes for one-half of a dose of a substance
to metabolize in the body and lose its pharmacological activity) of about two
hours (Hengstmann cited in Tang, Eisenbrand 1992). Again, one cannot assume a
direct relationship between the activity of intravenously administered, isolated
synephrine to the orally consumed bitter orange extracts found in dietary supplements.
Clinical Studies
Clinical trials on preparations containing bitter orange peel
extracts have basically targeted weight loss (at least two studies up to 2002),
increased thermogenesis (three trials), and its safety profile (one trial). A
recent comprehensive review of the medical literature by Stephen Bent and colleagues
at the University California at San Francisco revealed only seven randomized
clinical trials on bitter orange (Bent et al., 2004) This literature search identified a total
of 157 titles of scientific and medical papers published on bitter orange (or
in which bitter orange was mentioned). Six studies (three of which were published
as abstracts only) were excluded from the review because the tested preparations
contained the herb ephedra and/or ephedrine in addition to bitter orange (three
studies) or weight loss was not reported as a primary outcome measure (three
studies). One study (Colker et al., 1999) satisfied all inclusion criteria for the review
(see below). Bent and his colleagues concluded that, “This systematic review
found no evidence that the herb, citrus aurantium, is effective for weight loss.
Safety information is extremely limited, and, because citrus aurantium contains
the sympathomimetic drug msynephrine [sic*] (phenylephrine), consumption of the
herb may lead [emphasis added to
denote speculation] to increases in blood pressure, pulse, and the risk of adverse
cardiovascular events.” [*Note: bitter orange does not contain m-synephrine [metal-synephrine; it contains the p-synephrine [para-synephrine] isomer in its levo and devo rotary racemic
forms.]
The Bent review excluded one randomized, controlled, crossover
trial because the trial did not report a weight-loss outcome; it measured blood
pressure and pulse changes in 12 normal subjects after they drank fresh citrus
aurantium juice compared with a water
placebo (patients were not blinded) (Penzak et al. 2001, see below).
The trial by Colker et al. (1999), noted above, tested a bitter orange, caffeine and St. John’s
wort (SJW) combination. In a sixweek double-blind, randomized, placebocontrolled
trial, 23 healthy overweight (body mass index of 25 kg/m2; this is considered
overweight but not obese; the BMI parameter for obesity begins at 30 kg/m2+)
adults (age or sex not given) were assigned to one of three groups: (A) an herbal
mixture containing bitter orange (6% synephrine) 975 mg, St. John’s wort (Hypericum
perforatum) extract standardized to 0.3%
hypericin, 900 mg, and caffeine 528 mg; (B) a maltodextrin placebo; or (C) a
control group without placebo. The subjects used an American Heart Association
Step One diet and an exercise program three days per week under the supervision
of a trainer. Outcomes were assessed at baseline, three and six weeks, and included
change in weight, percent body fat, fat mass, and basal metabolic rate. Subjects
in Group A lost what the authors deem a significant amount of weight (1.4 kg)
and body fat (2.9%) compared to the placebo group, but the control group lost
about as much as the treatment group, thus rendering these results of questionable
value. The Bent review assessed the quality score of this trial at 3 out of a
possible 5 “because the randomization technique was not described and reasons
for the withdrawal of three subjects were not stated.”
Several small, unpublished clinical trials have been conducted
with bitter orange extract with other herbs and dietary supplement ingredients.
Since they have not been published in accessible medical, pharmacy, or nutrition
journals, it has not yet been possible for this writer to determine at the time
of this writing (end of January 2005) to what extent these unpublished studies
are accurately presented, or to what extent a peer review process that accompanies
the publication process would alter some of the trials’ conclusions. Some
of these unpublished trials are summarized below.
One small unpublished trial on 10 healthy adults (eight female,
two male) conducted by Miami Research Associates (www,miamiresearch. com),
using one serving of Xenadrine EFX (manufactured by Cytodyne LLC, Farmingdale,
NY) a combination product containing green tea extract, bitter orange extract
and numerous other ingredients, ingested after a meal, claimed to result in no
appreciable increase in blood pressure and showed an increase in metabolic rate
(Kalman et al., 2002a). Another
very small trial by the same research group tested the effects on blood pressure
and resting metabolic rate of Xenadrine EFX with two ephedra-containing supplements
in six normal, healthy adults (Kalman et al., 2002b).
The authors report that bitter orange-containing product does
not cause any significant change in heart rate, systolic or diastolic blood pressure
60 minutes after ingestion. They report, too, that the resting metabolic rate
was significantly elevated after administration of Xenadrine EFX, but with such
a small sample size, such results need a larger trial to show a significant effect.
A third trial by the same research group, tested on 16 overweight adults over
four weeks, employed Xenadrine EFX and exercise and mild reduction in caloric
intake (Kalman et al., 2003). Over 14 days, when compared to baseline values, those receiving
the Xenadrine EFX product had a lower appetite rating at day seven, but this
was non-significant by day 14. There were no significant negative effects on
blood pressure, heart rate, serial EKGs, blood sugar, renal function, hepatic
function or blood count in the two groups. Sleep quality was negatively impacted
in the EFX group (versus placebo), but whether this was due to the action of
the product or the combination of the product and exercise deserves further attention,
say the authors. Subjects in the EFX group compared to placebo experienced a
60.4% reduction in fatigue levels (p=0.0256).
An unpublished study for Jamieson Laboratories in Canada by
Penny Kendall-Reed, N.D., was designed to determine the effectiveness of a weight-loss
product called Ultra Slim Down (Jamieson Laboratories, Toronto, Ontario, Canada),
a product that was to be marketed as an agent that helps convert carbohydrates
and fat into energy and thus reduces body weight more effectively (Kendall-Reed,
2000). Ultra Slim Down consists of two main products, what the author terms a “carbohydrate
burner” and a “fat absorber” (chitosan). The ingredients in
the herbal carbohydrate burner include CitraMax (containing 125 mg hydroxycitric
acid [HCA] derived from the fruit of the Garcinia cambogia tree,
purportedly useful in helping the body convert dietary carbohydrates into energy
rather than storing them as fat). Other ingredients included 125 mg of a thermogenic
herb formulation known as Advantra Z (Nutratech, Wayne, NJ), derived from the
immature fruits of bitter orange, and 50 mg of cola nut (Cola nitida,
C. acuminata), a caffeine-containing herb
to provide enhanced energy levels. After 10 weeks, the study report states that
subjects in the group with the product only lost an average of 10.2 pounds (range:
10-12 pounds) and the group taking the product and employing exercise lost an
average of 14.5 pounds (range 3.5- 23 pounds); the control group (no product,
no exercise) lost 7.64 pounds (range 1-15 pounds).
The significance of these trials is unclear. It would be preferable
if the herbal materials tested were subjected to a larger group of test subjects
and the trials were published in peer-reviewed journals.
Finally, one U.S. trial on adults with normal blood pressure
tested Seville orange juice (SOJ), not
bitter orange peel (Penzak, 2001); note: Seville orange is another common name
for bitter orange. SOJ, like grapefruit juice, has been is used in medical trials
to “knock out” or deactivate the intestinal and hepatic enzyme substrate
cytochrome P450 (CYP) 3A4 in drug bioavailability studies. The purpose of this
particular study was to determine the synephrine and octopamine levels in SOJ and SOJ’s
cardiovascular effects in adults with normal blood pressure. The test subjects
consumed eight ounces of SOJ and water in a crossover fashion followed by a repeat
ingestion eight hours later. Various cardiovascular-related (hemodynamic) measurements
were assessed hourly for five hours after consumption of the juice, i.e., heart
rate; systolic, diastolic, and mean arterial pressure. The investigators stated
that the bitter orange juice had no significant effects on blood pressure or
pulse, but, according to Bent et al., “they
did not provide confidence intervals to exclude clinically important changes
in these hemodynamic measures.” (Bent et al 2004)
The SOJ was analyzed by high-performance liquid chromatography
(HPLC). The average level of synephrine was 56.9 +/- 0.52 micrograms per milliliter (computed
by Bent et al [2004] as approximately
13 to 14 mg of synephrine) and no octopamine was detected (consistent with other research,
despite some erroneous reports of its presence in bitter orange; see Chemistry
section in part 1, March 2004). Of particular interest is that the measurements
of the hemodynamics showed no significant difference between the water and the
SOJ groups, leading the authors to conclude that “SOJ ingestion by normotensive
subjects is expected to be safe.” (However, according to Bent et
al. [2004] the researchers “did not
provide confidence intervals to exclude clinically important changes in these
hemodynamic measures.”) Penzak et al. cautioned that people with severe hypertension, tachyarrhythmias
(increased, irregular heart beat), and narrow-angle glaucoma and those taking
MAOI drugs should avoid SOJ consumption as well as persons taking decongestant-containing
cold preparations (e.g., those with pseudoephedrine) should also refrain from
taking SOJ. (Because of its synephrine content, some of the same cautions apply to people
taking dietary supplements containing bitter orange peel extract. See below.)
Safety of bitter orange and synephrine
There is currently much concern being expressed in the media
about the overall safety and potential risks associated with bitter orange-containing
dietary supplements. Some warnings that are found in the professional literature
(e.g., Jellin 2002) are based mainly on
the chemical similarity of synephrine to ephedrine, without many data from actual adverse
event reports (AERs). The German Commission E monograph for bitter orange peel
says that there are no contraindications but that photosensitization may occur
in fair-skinned individuals (Blumenthal et al., 1998).
Curiously, writing over 100 years ago Felter and Lloyd state, “Large quantities
of it [bitter orange peel] have caused violent colic, convulsions, and even death.” (Felter
and Lloyd 1898) However, they do not give any indication regarding the level
of the purported toxic dosage.
One leading, authoritative text on Chinese pharmacological
research says that bitter orange “has a low toxicity and a wide safety
range.” (Chang & But 1987). It notes that most observations of cardiovascular
activity have occurred with intravenous administration of zhi shi decoction, synephrine, and N-methyltyramine in cases of treating
infections, anaphylactic or cariogenic shock resulting from other causes. These
preparations were deemed “effective when given intravenously, but not orally.” (Chang & But
1987). This observation by a respected Chinese research team tends to support
the question raised above about the oral availability of synephrine.
An unpublished acute oral toxicity study was performed on
rats to determine the relative safety of a single dose of a leading bitter orange
extract-containing supplement called Advantra Z, manufacturerd by Nutratech,
Inc., headquartered in Wayne, NJ (Douds, 1997). A limit test was performed wherein
one group of five male and five female rats received a single oral administration
of the test material at a dose of 10,000 mg/kg body weight and the rats were
observed until they were sacrificed after 14 days. No mortality occurred in any
of the rats during the test. The most notable clinical abnormalities observed
during the study included rough coat, decreased activity, congested breathing,
dark material around the facial area, decreased defecation, salivation, soft
stools and urine/fecal stain. These clinical abnormalities were observed during
the first few days after dosing, but then disappeared, with the exception of
residual slight hair loss which was still present in one animal for 14 days and
in another after seven days. A slight body weight loss was noted for one female
rat between days seven and 14 body weight interval. However, since the animals
were young adults and still growing, body weight gain was noted for all other
animals during the test period. No significant gross internal pathological findings
were observed at autopsy on day 14. Under the conditions performed in this test,
the acute oral LD50 (the amount of a substance required to kill 50% of the test
population) of Advantra Z was estimated to be greater than 10,000 mg/kg in the
rat. That is, this test concluded that it would require an extremely high dose
of Advantra to kill 50% of the rats, thereby suggesting the relative safety of
Advantra when given one time in a high dose.
A reliable book and database on herb safety (Brinker 2001,
2004) suggests the following contraindications for bitter orange based on empirical
reasons: stomach or intestinal ulcers, due to bitter orange’s tonic effect
on the gastrointestinal tract; in children, due to the presumption that excessive
doses can produce “toxic effects”; and ultraviolet or solarium light,
due to the potential photosensitizing effect. Additionally, the bitter orange
juice and/or its preparations are contraindicated in cases of severe high blood
pressure, rapid heart rate, and narrow-angle glaucoma due to its synephrine content (the
author notes this as speculative), even though 8 oz. of the juice did not affect
blood pressure or heart rate in normal subjects.
A U.S. Military “fact sheet” on bitter orange
contains information taken mainly from The Natural Medicines Comprehensive
Database (Jellin et al. 2002). The “fact” sheet makes the following statements: It
acknowledges that bitter orange is used in foods and is safe, but it states, “However,
bitter orange is not safe when used in high doses.” It states bitter orange
can cause hypertension and “cardiovascular toxicity” and that these
effects “can be exacerbated” when used with other stimulants (e.g., caffeine, coffee, cola nut, ephedra, guarana, and mate).
Regarding potential drug interactions, the military sheet states that bitter
orange can increase stomach acid and can thus interfere with antacid (calcium
carbonate, e.g., Tums, and aluminum/magnesium
hydroxide (Maalox) as well as ulcer medications (e.g., Prilosec,
Zantac et al.). These interactions appear speculative, at least
at this time. Other potential interactions noted by the fact sheet include the
following drugs: anti-anxiety drugs (e.g., alprazolam [Zanax]), blood pressure medications, cholesterol-lowering
drugs (the statins), decongestants, antidepressants, allergy drugs, HIV drugs,
anti-fungals, sedatives, anti-nausea drugs, steroids, weight-loss drugs, and
erectile dysfunction drugs (sildenafil aka Viagra). These interactions warrant
attention, as the inhibition by 40% of the isozyme CYP3A4 of the P-450 enzyme
system by bitter orange would probably increase the activity of drugs that are
substrates to CYP3A4 enzymes. Brinker’s herb-drug interactions database
also notes these potential interactions (Brinker 2004).
Regulatory Issues
Bitter orange flowers, peel, and peel oil are generally recognized
as safe (GRAS) as foods according to the
Food and Drug Administration (FDA). Viewing the websites of FDA’s Investigations
Operations Manual (revised March 3, 2003) produced by the FDA’s Office
of Regulatory Affairs shows that the flowers and peel of bitter orange are listed
as safe food ingredients (FDA Inspection Manual, 2003). In the FDA’s “EAFUS:
A Food Additive Database” (“Everything” Added to
Food in the United States” (EAFUS)
both bitter orange peel extract and bitter orange peel oil are considered “ASP”, i.e., “Fully up-todate toxicology information has been
sought.” bitter orange peel extract is noted as document number 2486 and
bitter orange peel oil is number 2487, denoting the PAFA (Priority-based Assessment
of Food Additives) database number of the Food Additive Safety Profile volume containing the printed source information concerning
the substance. Bitter orange peel oil is listed with the Chemical Abstract Service
(CAS) Registry Number (#068916-04-1) and bitter orange peel extract has a numerical
code assigned by the FDA’s Center for Food Safety and Nutrition (CFSAN)
(#977081-87-0) since it does not have a CAS Registry Number. Both substances
are specifically listed in Title 21 of the Code of Federal Regulations (FDA
EAFUS, 2004). Most of the extracts found in dietary supplements are usually derived
from the whole, immature fruit.
Much of the current interest in bitter orange has been a result
of numerous articles in the media, many of which have focused on the fact that
bitter orange has become the primary substitute ingredient for ephedra in ephedra-free
products. While many articles have reported on the increased popularity of bitter
orange as part of the post-ephedra ban news coverage, some articles and editorials
seem to have jumped on bitter orange as the media’s potential new “whipping
boy.” various writers making what is probably the erroneous conclusion
that bitter orange is equal to ephedra in activity and potential toxicity. Such
a rush to judgment does not appear to be warranted by the available evidence.
An example of the media’s targeting of bitter orange
and synephrine is epitomized in a commentary in Business Week: “With the potential threat of harm from ephedra-free products,
leaving the law unchanged is too great a risk. But unless the FDA can argue that
the synephrine in bitter orange is pharmacologically close enough to ephedrine
to
|