Download Synephrine, Octopamine and Caffeine Health Risk

To: Scott Sawler, Director General, Natural
Health Products Directorate (NHPD)
Security – Classification: HC Protected
Prepared By: Robin Marles, NHPD
Date Created: 2011-01-27
Date Completed: 2011-05-16
Synephrine, Octopamine and Caffeine Health Risk Assessment (HRA) Report
Issue
Assessment of the potential risks to health from natural
health products containing synephrine and/or octopamine
in combination with caffeine.
HC File Number
172091
Requested By/Date of Request
Christine Zaczynski, Health
Products and Food Branch
Inspectorate (HPFBI)
2011-01-27
Consulted With/Date of
Consultation(s)
Marketed Biologicals,
Biotechnology and Natural Health
Products Bureau, Marketed Health
Products Directorate (MHPD)
2011-02-28
SUMMARY OF PRODUCT INFORMATION
various products not licensed for sale in Canada
Name of Product(s) &
Identification Number (if any)
Natural Health Products
Type of Product
various
Common Name (if any)
Medicinal/Active Ingredient(s) Synephrine and/or Octopamine and Caffeine
various
Dosage Form(s)
various
Strength(s)
Oral
Route of Administration
Weight loss aid is the primary indication
Proposed Indication(s)
Adults
Proposed Sub-population(s)
various
Non-medicinal/active
Ingredient(s) (if applicable)
various
Manufacturer/Sponsor
various
Manufacturer Site Licence
Information and Number (if
applicable)
REVIEWER’S DECISION
Health Risk Classification &
Recommendation
Types III, II and possible I as specified for different
product compositions and conditions of use, below.
APPROVALS
Revised and Approved By
Robin Marles, Director, Bureau of Clinical Trials and
Health Sciences, Natural Health Products Directorate
(NHPD)
Signature
Date Review Approved
2011-05-16
Synephrine Octopamine Caffeine HRA
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Executive Summary
Citrus aurantium Peel
Based on the evidence reviewed above, the botanical material Bitter Orange peel, at the doses
typically used in herbal medicine and food, is not considered to pose any risk to the health of
consumers.
p-Synephrine Alone
At doses up to 50 mg/day in healthy adults, p-synephrine is classified as Type III, except in cases
where the necessary cautionary statements (i.e. contraindicated in children, pregnancy, and
breast-feeding, do not use if you are taking blood pressure medications (either hypertensives or
antihypertensives), thyroid medications, sympathomimetics, or monoamine oxidase inhibitors
(MAOIs)) are lacking, which would result in a risk classification of Type II.
At doses above 50 mg/day, p-synephrine approaches the dose used as a prescription drug in
Europe for the treatment of hypotension. While it is possible to be exposed to a dietary source of
as much as 70 mg of p-synephrine from a cup of Cleopatra mandarin orange juice, this is not a
common item in the diet and the dose-response curve for p-synephrine between 50 mg and
therapeutic doses of the racemic tartrate are not adequately characterized to be categorical as to
safety. Therefore, in the absence of a product-specific review of safety under specific
recommended conditions of use, as would be accomplished through assessment of a product
licence for market authorization, the application of precaution is a legitimate decision making
approach within risk management. Such unauthorized products are therefore classified as a Type
II risk to health.
p-Synephrine and Caffeine
Products providing 40 mg/day or less of p-synephrine plus 320 mg/day or less of caffeine, are
classified as Type III, except in cases where the necessary cautionary statements (i.e.
contraindicated in children, pregnancy, and breast-feeding, do not use if you are taking blood
pressure medications (either hypertensives or antihypertensives), thyroid medications,
sympathomimetics, or monoamine oxidase inhibitors (MAOIs)) are lacking, which would result
in a risk classification of Type II.
Products exceeding either threshold dose or products lacking the cautionary statements (i.e.
contraindicated in children, pregnancy, and breast-feeding, do not use if you are taking blood
pressure medications (either hypertensives or antihypertensives), thyroid medications,
sympathomimetics, or monoamine oxidase inhibitors (MAOIs)), are classified as a Type II risk
to health.
p-Synephrine, Caffeine and Other Stimulants
Such products have been implicated in many serious adverse reaction case reports. Causality is
not likely due to the p-synephrine content on its own, rather to other ingredients such as
octopamine in high doses or thyroid drugs such as iodotyrosine. The risk to human health must
be assessed on a case by case basis. Given the nature of the observed adverse reactions, it is
probable that some of these products will be assessed as posing a Type I risk to health.
Synephrine Octopamine Caffeine HRA
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p-Octopamine
Based on its known pharmacology, p-octopamine at doses up to 50 mg/day in healthy adults is
classified as Type III. At doses above 50 mg/day, due to the paucity of human clinical data, in
the absence of a product-specific review of safety under specific recommended conditions of use,
as would be accomplished through assessment of a product licence for market authorization, the
application of precaution is a legitimate decision making approach within risk management.
Such unauthorized products are therefore classified as a Type II risk to health.
Exacerbating Conditions
Due to the extremely limited evidence for the safety of chronic use of p-synephrine at doses
higher than 50 mg or in combination with caffeine or other ingredients in vulnerable
subpopulations, the following cautionary statements (or words to these effects) should be on
product labels to mitigate the risk of potentially serious adverse reactions:
 Contraindicated in children, pregnancy, and breast-feeding.
 Do not use if you are taking blood pressure medications (either hypertensives or
antihypertensives), thyroid medications, sympathomimetics, or monoamine oxidase
inhibitors (MAOIs).
Consistency of Approach with Previous NHP HRAs
The recommended Health Risk Classification criteria above are consistent with the Health Risk
Assessments (Health Hazard Evaluations) previously prepared by Health Canada with respect to
the products Thermonex (Type I, 2004-04-13), Slim System 8 (Type II, 2004-12-20), No. 1
Protocole Minceur (Type III, 2005-06-10), MetaSlim (Type III 2006-02-22), Synerate (Type I,
2010-12-31), and Lipo-6X (Type I, 2011-01-25).
Conclusions
There are a number of limitations that are common to all the available clinical studies, including:
 The sample sizes of the studies are extremely small. Although the possible cardiovascular
effects to products in this class are potentially very serious, they are also fairly rare. The
available studies are not sufficiently broad in scope to support the safety in a general
consumer population, especially when the population targeted for these products consists of
largely overweight/obese individuals, who are subject to various co-morbidities. This
limitation is inherent to all available randomized, controlled trials. In effect, appropriate
evidence for safety, especially for rare adverse events, should come by way of sufficient
epidemiological studies;
 In addition to the limited sample sizes, the study populations are also generally healthy, even
if some studies include overweight individuals. This adds further to the incomparability of
available studies and extrapolation to the general population;
 None of the studies include a justification for their sample sizes, nor an indication of power.
This is a critical oversight, as it calls into question all of the findings. Lack of an effect could
very well be a genuine lack of an effect, or simply an inability to detect an effect;
 The studies are all of very short duration – another inherent deficiency seen when using
randomized, controlled trials to support safety. As the nature of the cardiovascular events
could depend on long-term exposure (e.g., chronic sympathetic over-stimulation), the shortterm studies are not adequate to support long-term safety. The authors of Seifert et al. (2011)
comment that, “longer term studies are required to assess [the effects on heart rate and blood
Synephrine Octopamine Caffeine HRA
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pressure] under conditions similar to those encountered when using the product in
conjunction with a long term weight loss program.”
In summary, this Health Risk Assessment does not address the issue of efficacy, which must be
assessed through the product licensing process for each individual product.
However, based on new clinical studies and published reviews of safety information, it has been
possible to revise the synephrine and caffeine recommendations prepared previously by Health
Canada (2010c) in order to reduce unnecessary compliance actions on products that do not
present as serious a risk to health as had been judged previously. This will allow resources to be
focused better on compliance and enforcement of more risky products.
Issue Identification
In seeking an alternative to ephedra for use in weight-loss products after reports of serious
adverse reactions and consequent compliance and enforcement actions by regulatory authorities
in various countries, the history of use of citrus fruit consumption for weight loss has been
extensively investigated, with much attention focused on Bitter Orange and its proto-alkaloids
synephrine and octopamine (Preuss et al. 2002). While there is some preliminary evidence from
animal, in vitro, and human studies for limited efficacy and safety of bitter orange, some
potential safety issues have been identified with the consumption of synephrine or related
sympathomimetics particularly when combined with caffeine. There are unlicensed natural
health products (NHPs) currently on the Canadian market and Product Licence Applications
(PLAs) currently under review that include synephrine and/or octopamine, or Bitter Orange peel
which is a source of these substances, with caffeine or sources of caffeine such as cocoa, cola,
guaraná, maté, or green tea.
The purposes of this HRA are to develop risk classifications and relevant risk mitigation
strategies, including public communication and guidance for compliance and enforcement
actions, for unauthorized products containing synephrine and/or octopamine, with or without
caffeine, and with or without additional stimulants.
The HRA will then be used to develop basic assessment requirements for the evaluation of
product licence applications for NHPs that include these ingredient combinations.
This HRA is not intended to apply to any product that has already been licensed by the Natural
Health Products Directorate (NHPD), unless the marketed product is not in compliance with its
approved conditions of use and labelling. Licensed products should be safe and effective when
used according to all of the recommended conditions of use.
Health Risk Assessment
Synephrine Octopamine Caffeine HRA
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The main potential cause for concern relates to suspected involvement of human oral
consumption of products containing synephrine and/or octopamine, with or without caffeine, in
cardiovascular serious adverse reactions.
Hazard Identification & Characterization
Occurrence of Synephrine, Octopamine and Related Substances
Bitter Orange (also known as Seville Orange, Citrus aurantium L., Rutaceae) peel extracts are
well-known sources of synephrine and other proto-alkaloids, shown together with ephedrine
(mainly coming from Ephedra species) and the human neurotransmitters epinephrine and norepinephrine (also known as adrenaline and noradrenaline, respectively) in Figure 1 to facilitate
comparison of their chemical structures.
Synephrine Octopamine Caffeine HRA
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OH
OH
NH
NH
CH3
CH3
CH3
HO
R-(-)-Synephrine
(1R,2S)-(-)-Ephedrine
OH
OH
HO
NH2
HO
NH
CH3
HO
R-(-)-Octopamine
Epinephrine (Adrenaline)
OH
HO
OH
NH
HO
NH2
CH3
HO
R-(-)-Phenylephrine (meta-Synephrine)
Norepinephrine (Noradrenaline)
CH3
N
NH2
CH3
HO
HO
Hordenine
Tyramine
Figure 1. Molecular structures of synephrine, octopamine and related adrenergic agonists.
Synephrine has also been isolated from other members of the citrus family (Rutaceae) including
sweet orange (Citrus sinensis (L.) Osbeck), mandarin orange (Citrus reticulata Blanco), Murcott
orange (C. reticulata × C. sinensis), Satsuma mandarin (Citrus unshiu Marcow.), Cleopatra
mandarin (Citrus reshni hort. ex Tanaka), tangerine (Citrus tangerina Tanaka), Mediterranean
tangerine (C. deliciosa Ten.), tangelo (Citrus ×tangelo J. W. Ingram & H. E. Moore), temple
Synephrine Octopamine Caffeine HRA
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orange (Citrus temple hort. ex Yu. Tanaka), Hassaku orange (Citrus hassaku hort. ex Tanaka),
common lemon (C. limon (L.) Burm. f.), sweet lemon (Citrus limetta Risso), rough lemon
(Citrus jambhiri Lush.), Meyer lemon (Citrus meyeri Yu. Tanaka), manderin lime (C. limonia
Osbeck), calamondin (×Citrofortunella microcarpa (Bunge) Wijnands), Troyer citrange
(×Citroncirus webberi J. W. Ingram & H. E. Moore), evodia (Evodia rutaecarpa (A. Juss.)
Benth. reclassified to Tetradium ruticarpum (A. Juss.) T. G. Hartley). Synephrine has also been
isolated from plants in other families including the Amaryllidaceae (Amaryllis Amaryllis vittata
L’Hér. reclassified as Hippeastrum vittatum (L’Hér.) Herb., Amazon lily Eucharis ×grandiflora
Planch. & Linden, and Blood lily Haemanthus katherinae Baker reclassified as Scadoxus
multiflorus (Martyn) Raf. subsp. katherinae (Baker) Friis & Nordal) and Moraceae (rubber tree
Ficus bengalensis L.) (Wheaton and Stewart 1965, 1969, 1970; Hosoda et al. 1990; Blumenthal
2004-2005; Arbo et al. 2008; Dragull et al. 2008; Hibino et al. 2009).
Octopamine is present naturally in much lower levels than synephrine (usually less than 0.03 %)
in citrus juices and extracts; it was below the limit of quantification in fresh and dried fruit of
Bitter Orange (Pellati et al. 2002). It was detected in trace amounts in temple orange and Murcott
orange juices, 1 mg/L in Dancy and Robinson tangerine juices, 2 mg/L in Cleopatra mandarin
juice and 4 mg/L in Meyer lemon juice (Stewart and Wheaton 1964; Wheaton and Stewart
1965). It has also been isolated from papyrus (Cyperus papyrus L., Cyperaceae) leaves at 17
mg/kg fresh weight and nutgrass (Cyperus rotundus L.) leaves at 91 mg/kg fresh weight, leaves
of the asparagus relative liriope (Liriope spicata (Thunb.) Lour., Asparagaceae) at 20 mg/kg
fresh weight and bell pepper (Capsicum frutescens L., Solanaceae) leaves at 234 mg/kg fresh
weight (Wheaton and Stewart 1970).
Bitter Orange also contains the protoalkaloids tyramine, hordenine and N-methyltyramine
(Nelson et al. 2007).
Three positional isomers of synephrine exist (Figure 1): para-, meta- and ortho-synephrine.
These isomers differ in the position of the phenolic hydroxyl group, which impacts on the
pharmacological activity of these compounds (Allison et al. 2005).
In mammals, p-synephrine and m-synephrine occur naturally in the adrenal gland and probably
in the nerves of the heart and brain although at extremely low concentrations; p-octopamine is
found at concentrations of 6-60 pmol/g in the sympathetic nervous system with norepinephrine
(NE), where it functions as a co-neurotransmitter or modulator of NE activity in the sympathetic
nervous system (Ibrahim et al. 1985; Williams et al. 1987; Brown et al. 1988; Evans et al. 1988).
The natural occurrence of o-synephrine has not been reported to date (James et al. 1983; Allison
et al. 2005). Both m- and o-octopamine have also been reported to occur naturally in vertebrates
(James et al. 1983; Brown et al. 1988; Evans et al. 1988). Octopamine is an important
neurotransmitter in invertebrates (it was first isolated from the octopus, hence the name) where
with tyramine it plays the complex variety of roles that epinephrine and norepinephrine play in
vertebrates (Roeder et al. 2003). R-(-)-p-Synephrine, through its stimulation of NE release, may
play a role in mental health by providing an endogenous antidepressant-like effect (Kim et al.
2001). Octopamine may be an important biomarker for certain pathogenic processes, since it has
been reported to occur at mean levels of 0.2 to 0.4 ng/mL in the plasma of healthy subjects, but
has been seen as an abnormality at concentrations above 3.2 ng/mL in hepatic encephalopathy
Synephrine Octopamine Caffeine HRA
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(Rossi-Fanelli et al. 1976), with rare extremes up to 59.5 ng/mL in cirrhotic patients with hepatic
coma (Hörtnagl et al. 1981), and in renal disease at 1.9 ng/mL increasing to 2.7 ng/mL during
dialysis (Kinniburgh and Boyd 1979); octopamine production may be deficient in some cases of
depression as suggested by urinary output of metabolites (Sandler et al. 1979).
The p-synephrine found in Bitter Orange should not be confused with m-synephrine, a synonym
for phenylephrine (also known as Neo-Synephrine), a sympathomimetic drug used as a nasal
decongestant, midriatic and cardiotonic (Sweetman 2007; NIH 2004) that can induce reflex
bradycardia (Martindale 2007; Keys and Violante 1942). There is evidence that some
manufacturers may be adulterating Bitter Orange extracts with m-synephrine, since Allison et al.
(2005) found both m- and p- isomers in a commercial product purportedly containing synephrine
from C. aurantium. Studies at the University of Mississippi found only p-synephrine in C.
aurantium (Ikhlas Khan, National Center for Natural Products Research, University of
Mississippi, e-mail to V. Hurry, 2007-10-02 9:08 AM). Roman et al. (2007), using a singlelaboratory validated method, found that octopamine, phenylephrine, tyramine, N-methyltyramine
and hordenine were all below the limit of quantification (about 300 µg/g except about 600 µg/g
for phenylephrine) in National Institute of Standards and Technology reference samples of Citrus
aurantium powdered lyophilized Bitter Orange raw material and a powdered Bitter Orange fruit
extract, while for Nutratech C. aurantium raw material, octopamine averaged 554 µg/g and Nmethyltyramine averaged 1200 µg/g; phenylephrine, tyramine and hordenine were below the
limit of quantification in these samples and in two commercial Bitter Orange dietary
supplements.
Using chiral HPLC chromatography, Pellati et al. (2002) found l-synephrine, also known as (-)synephrine, the R-enantiomer, present in all samples analyzed of Citrus aurantium L. var. amara
L. fresh fruits, dried fruits, dried extracts, and herbal products. A significant amount of dsynephrine, also known as (+)-synephrine, the S-enantiomer, was found in fresh fruits and some
commercial products. They found from a heat stability study that synephrine was not likely to be
racemized at temperatures within the range usually used for extraction procedures (refluxed in
water at 100oC for 24 h), but in a subsequent investigation (Pellati et al. 2010) they revised this
position by concluding that racemization of the naturally occurring R-(-)-synephrine is possible
at high temperature at both acidic and basic pH values, and that the presence of an organic cosolvent also affected racemization.
Evidence from Animals, in vitro Studies, Models & Bench Testing
Mechanisms via Receptor Binding
Central nervous system biogenic amine systems have been studied extensively with respect to
their effects on feeding behaviour, energy balance and weight management (Nelson and Gehlert
2006). Food intake can be stimulated or inhibited depending on which type of adrenergic
receptors (ARs) in the brain are affected: NE activation of α1-ARs in the paraventricular nucleus
decreases food intake, while NE activation of α2-ARs, which are coupled through G proteins to
modulate cyclic adenosine monophosphate and calcium channels, will stimulate food intake, but
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specific α2-AR antagonists have not been shown to have significant or consistent effects on
human body weight. NE stimulation of β2-ARs in the perifornical area will also decrease food
intake. The β3-AR plays a key role in thermogenesis, and increased sensitivity of the β2-AR to
NE stimulation also plays a role in lipolysis (Bray and Greenway 1999). Unfortunately, the
lipolytic effect of selective β3-AR agonists does not appear to persist in humans due to either lack
of recruitment of β3-AR responsive tissue, a down regulation of β3-ARs, or both, so human trials
have been disappointing (Bray and Greenway 2007).
Synephrine has been shown, in vitro, to interact directly with the α1-ARs and cause contraction
of the rat aorta, anococcygeus (pair of thin sheets of smooth muscle that insert into the rectum),
as well as the guinea pig atria and trachea (Brown et al. 1988). Varma et al. (1995) used
endothelium-denuded strips of rat aorta to show that in the presence of blockade of both α-AR
(by benextramine) and β-AR (by propranolol), significant vasorelaxation (66% to 92%) was
caused by tyramine > l-ephedrine > synephrine > octopamine. p-(-)-Synephrine’s interaction
with α1- and α2-ARs, however, is much weaker than phenylephrine, and both are weaker than
NE: phenylephrine is 4 to150-fold less active than NE, and synephrine is 30 to 1,000 fold less
active than NE, depending on the tissue in which the receptor is located. In all circumstances, the
meta- forms of synephrine have much greater direct binding ability than do the para- forms, and
the (-) levo forms have greater direct activity than the (+) dextro forms generally in 1-3 orders of
magnitude (Brown et al. 1988). Synephrine’s effect at the α1-ARs is supported by the reversal of
effects with an α1-antagonist (Prazosin) (Fugh-Berman and Meyers 2004). Further studies have
confirmed that synephrine binds to human α1A-, α2A- and α2C-AR subtypes with relatively low
affinity, acting as a partial agonist at the α1A-AR (EC50 = 4 µM, maximal response at 100 µM
that was equal to 55.3% of the L-phenylephrine maximum) and as a lower activity partial
antagonist at the α2A- and α2C- ARs (Airriess et al. 1997; Ma et al. 2010).
At the β1-AR in guinea pig atria, the rank order for the activities of the (-)-stereoisomers of the
phenylethylamines was found to be NE > m-synephrine (100 fold) > m-octopamine = poctopamine (6000 fold) > p-synephrine (40,000 fold). The (+)-sterioisomers were were 1-2
orders of magnitude less active than their (-)-counterparts. At the β2-AR in guinea pig trachea the
four (-)-stereoisomers were more than four orders of magnitude less active than NE and the (+)stereoisomers had no detectable activity in concentrations as high as 10-4 M (Jordan et al. 1987).
Octopamine has been reported to have lipolytic activity in isolated rat fat cells although only at
concentrations greater than 0.1 µM (Nakano et al. 1969). Despite some evidence for octopamine
stimulation of α1- and α2-ARs from animal models (e.g. Brown et al. 1988; Airriess et al. 1997),
it has only a very weak affinity for the human α2A-AR and can be considered to be devoid of
functional human α2-AR agonism (Fontana et al. 2000). Visentin et al. (2001) demonstrated that
in rat fat cells, (±)-octopamine stimulated lipolysis and counteracted insulin lipogenic action via
β3-AR stimulation, but, on the other hand, stimulated glucose uptake by a mechanism dependent
on octopamine’s oxidation by monoamine oxidase or semi-carbazide-sensitive amine oxidase.
Some of the central nervous system effects of octopamine have been attributed to its stimulation
of central dopaminergic and noradrenergic systems, and its reduction of cerebral concentrations
of NE and gamma-aminobutyric acid (GABA); inhibition of the activity of the synthesizing
enzyme glutamate decarboxylase was observed (Jagiello-Wojtowicz and Chodkowska 1984).
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Octopamine also has greater sympathomimetic activity associated with the R-(-)-enantiomer than
the S, increasing blood pressure and having positive chronotropic and inotropic effects on the
heart of experimental animals such as the dog and cat, but is weaker in its effects than
norepinephrine (David and Coulon 1985).
Carpéné et al. (1999) reported that synephrine and octopamine exhibited lipolytic effects in rat,
hamster, guinea pig and human adipocytes, but only at high concentrations (0.1 to 1 mM).
Synephrine’s lipolytic effects have been suggested to be likely attributable to β1-AR and/or β2AR stimulation since lipolysis could be induced in the guinea pig, a species lacking β3-AR
responsiveness, and was suppressed by selective β1-AR and β2-AR antagonists but only poorly
by a selective β3-AR antagonist. Synephrine and octopamine had similar levels of intrinsic
activity compared to the model β3-AR agonist isoprenaline with a 2-fold lower affinity for
human β3-AR than NE. However, the evidence indicates that octopamine is a selective β3-AR
agonist.
In a subsequent paper from the same research group, Mercader et al. (2011) reported that their
observations of lipolysis appear contradictory to synephrine having α2-AR antagonist activity
since it was unable to improve epinephrine-induced lipolysis in human fat cells and did not
totally prevent bromoxidine-induced antilipolysis. They noted that partial agonism of α2-ARs by
synephrine cannot be excluded but its very poor affinity to the α1-, α2a- and α2c-ARs make
resolving this issue of doubtful value. Compared to the 7-fold increase in lipolysis seen as the
maximal response (defined 100%) from the β-AR agonist isoprenaline at 10 µM (2.45 µg/mL) in
human adipocytes, synephrine provided 33% of the maximal response and octopamine provided
52% of the maximal response, but they had very low potency compared to isoprenaline with
activity detected only at concentrations >10 µg/mL. Octopamine was additive to isoprenaline,
synephrine was not. The mechanism of action of octopamine is by activation of β3-ARs but
unlike rat adipocytes, human fat cells have only a weak β3-AR responsiveness. Tyramine and Nmethyltyramine had antilipolytic activity. The authors conclude that based on their in vitro data,
although having lower intrinsic activity that octopamine, synephrine has a much higher
concentration so it can be considered the predominant active lipolytic component of Bitter
Orange. However, the benefit/risk ratio remains to be established due to the high doses needed to
achieve an effective concentration in the human adipocytes compared to the toxic dose. The
authors recognized that a potential weakness of their study was their use of racemic synephrine
rather than the R-(-)-enantiomer but also noted that racemic synephrine is generated by
commercial extraction procedures, so their results may in fact be relevant to products on the
market. Based on these results, the presence of tyramine and N-methyltyramine in weight-loss
products is not desirable.
Since synephrine and octopamine are commonly suggested to be pharmacologically similar to
ephedrine due to the relatedness of their chemical structures, it is instructive to review the
receptor binding of ephedrine. By convention, ephedrine is the name for the two enantiomers
with opposite stereochemistry around the two chiral centres (1R,2S and 1S,2R, see Figure 1),
while pseudoephedrine has the same stereochemistry around the two chiral centres (1R,2R and
1S,2S). Commercial synthetic ephedrine may be racemic but natural ephedrine is the (-)- or lstereoisomer, with the (1R,2S) configuration. The stereochemistry is important as it dramatically
affects the pharmacology, as demonstrated in the studies below.
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The beneficial and adverse effects of ephedrine and related analogues are known to be mediated
via the α- and β-ARs and may be elicited by either direct interactions with the receptors as
agonists or antagonists or indirectly by either causing a release of endogenous catecholamines
and/or by preventing their neuronal reuptake. The relative contribution of these direct and
indirect interactions to the pharmacological effects of the ephedrine isomers in humans in vivo
has remained controversial (Ma et al. 2007). Rothman et al. (2003) found that (-)-ephedrine’s
most potent action was substrate activity at NE transporters. Using cloned human ARs expressed
in animal tissues, it has been determined that (-)-ephedrine is generally more potent than its
enantiomers to α-ARs (Ma et al. 2007) and β-ARs (Vansal and Feller 1999), and that (-)ephedrine showed the highest intrinsic activity at human β2-AR and also showed significant
agonist activity at β1-AR but probably clinically inconsequential agonist activity at the human β3AR (Vansal and Feller 1999), and even where β1- and β2-AR activity has been shown, it is still at
least an order of magnitude lower than NE due to low affinities for the receptors (Rothman and
Baumann 2005). At cloned human α1A-, α1B-, α1D-, α2A-, α2B-, and α2C-ARs, (-)-ephedrine had
only a weak partial agonist activity (at >10-4 M) and moderate antagonist activities on the α-AR
subtypes. This is in contrast to rodent cell lines in which (-)-ephedrine was seen to have an
agonist effect on β3-AR and α1A-ARs, possibly related to a greater density of receptors (Ma et al.
2007). Furthermore, in rodents gene knockout techniques provided support for direct mediation
through α-ARs of pressor responses to (-)-ephedrine rather than through effects on the release of
NE (Liles et al. 2007). In humans, (-)-ephedrine may block α1A-ARs and act as antagonists of
presynaptic α2A/2C-ARs, interfering with presynaptic NE uptake, thus enhancing the synaptic
concentration of NE and its effects (Ma et al. 2007).
In a further mechanistic study, Fang et al. (2003) used a model of ventricular myocytes of guinea
pigs to show that Citrus aurantium extract could increase the L-type calcium current and
promote the opening of the calcium channel at low concentrations or inhibit the L-type calcium
channel and depress its opening at high concentrations.
Hibino et al. (2009) studied the effects of a water-extract of Evodia rutaecarpa (standardized to
~20% synephrine) on the contraction of aortic strips, isolated from young (7- or 13-week-old)
Wistar rats. When expressed in terms of synephrine content, it was found that a significant
increase in contraction (vs. vehicle) was seen at 3 × 10-7 M, with a maximal effect (i.e., ~90% of
the maximum tension induced by 60 mM K+) at 1 × 10-5 M. Hibino et al. (2009) presented
evidence from the use of selective antagonists to suggest that synephrine may also have
serotonergic activity, primarily at 5-HT2A receptors (perhaps to a lesser extent at 5-HT1D), which
may contribute to vasoconstrictive activity. Assuming a molecular weight of 167.2 g/mole for
synephrine, these concentrations equal 0.05 to 1.7 ng/mL, respectively. These concentrations are
similar to maximal blood concentrations of ~2 ng/mL, found in humans, after having consumed
46.9 mg of synephrine (Haller et al., 2005).
With respect to the mechanism of the addition of caffeine to ephedrine or synephrine, caffeine is
a non-selective adenosine receptor antagonist, and blockage of adenosine’s pre-synaptic activity
would lead to the release of catecholamines, which would act on the adrenergic receptors. Kim et
al. (2001) demonstrated the ability of p-synephrine to stimulate NE release. Inhibition of the
adenosine receptors in the heart (A1) would promote contractility and activity in the sinoatrial
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node and atrioventricular node (Stiles 1986), and inhibition of adenosine receptors in the smooth
muscle vasculature (A2) would result in vasoconstriction (Mort and Kruse 2008; Higdon and Frei
2006; Mandel 2002; Stiles 1986). In vitro experiments have shown that the sympathomimetic
activity of synephrine and octopamine is enhanced upon coadministration of caffeine or other
methylxanthines (Kalsner 1971; Fischer and Florey 1987).
At high doses, caffeine may cause hypotension due to β-AR activation and tachycardia due to the
release of catecholamines (Benowitz 1990). Caffeine is also suggested to inhibit the enzyme
phosphodiesterase, responsible for inactivating cAMP (cyclic 3,5-adenosine monophosphate),
leading to increased adrenergic effects (Kalman et al. 2002; Brent et al. 2005). The latter is not
thought to occur at doses of caffeine in food or drink; however, this may occur with higher doses
of caffeine present in natural health products (Mort and Kruse 2008; Dulloo et al. 1992).
Thus, caffeine and other methylxanthines prevent the body from becoming resistant to the effects
of phenylpropamines by inhibiting the adenosine receptor and phosphodiesterase (Bray and
Greenway 1999). These results suggest that synephrine and octopamine interactions with
caffeine in humans are likely to be similar to the reported ephedrine and caffeine interactions
(e.g. Young et al. 1998) although to a much lesser degree, i.e., requiring much higher doses to
observe the same effects.
With respect to structure-activity relationships, key differences that affect the three-dimensional
structure (steric hindrance) and the distribution of hydrophobic potential across the molecule,
both affecting receptor site binding, distribution in the body such as the ability to cross the
blood-brain barrier, and activity, include the para-hydroxyl functional group of p-synephrine and
p-octopamine which is absent in (-)-ephedrine, the basic carbon skeleton with synephrine and
octopamine being phenylethylamines while ephedrine is a 2-methylamino-1-phenylpropanol, and
the secondary amine functional group of synephrine and ephedrine while octopamine has a
primary amine. For example, the presence of the para-hydroxyl functional group and the lack of
the additional methyl group on the side chain greatly decrease the lipid solubility of psynephrine compared with ephedrine, resulting in little transport into the central nervous system
compared with ephedrine. The larger the size of the alkyl group linked to the amine group of the
side chain, the greater the affinity for the β-AR (Rossato et al. 2011). Differences in steric
hindrance and receptor binding creating pharmacodynamic differences also apply to positional
isomers such as m-synephrine compared to p-synephrine (Brown et al. 1988; Colker et al. 1999;
Stohs et al. 2011a).
In summary, there are both qualitative and quantitative differences in the mechanism of action of
ephedrine compared to synephrine, octopamine and related substances, and these differences are
further complicated by significant differences between rodent and human receptor experimental
models. In humans, ephedrine has β1- and β2-AR agonist activity, no significant β3-AR activity,
and α2-AR antagonist activity, at least one fold less potent than NE, but due to low affinity for
these receptors it acts mainly through increasing presynaptic NE concentration. Synephrine is a
partial agonist at α1A-AR and partial antagonist at the α2A- and α2C- ARs, 30 to 1,000 fold less
active than NE, and synephrine is also a partial agonist at β1-, β2-ARs although it is 40,000 fold
less active than NE, and a partial agonist at β3-ARs although only half as potent as NE.
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Synephrine also acts by stimulating NE release. Octopamine is a selective β3-AR agonist,
although with a 2-fold lower affinity than NE.
Preclinical Pharmacology and Toxicology
In an acute study using a model of portal hypertension in Sprague-Dawley rats (Huang et al.
1995), intravenous unripe Bitter Orange (aqueous extract, 7.5 to 30 mg/kg body weight) and
intravenous synephrine (0.57 to 2.28 mg/kg body weight) were shown to significantly increase
mean arterial pressure and decrease portal vein pressure in a dose-dependent manner. The
increase in mean arterial pressure following Bitter Orange infusion was comparable to that with
synephrine. The mechanism was suggested to be by way of arterial vasoconstriction.
In a subchronic study using two models of portal hypertension in Sprague-Dawley rats (Huang
et al. 2001), oral synephrine (1 mg/kg body weight per day for 8 days) significantly increased
mean arterial pressure (MAP), systemic vascular resistance and portal tributary vascular
resistance (n=7 per group, 42 total) (p<0.05). Cardiac index, portal vein pressure, and portal
tributary blood flow were significantly decreased (p<0.05). No significant effects in body
weight, heart rate, gross changes, or mortality were observed. It was suggested by the authors
that the observed effects were due to synephrine’s activation of the α1-ARs, resulting in
vasoconstriction of the splanchnic or mesenteric arteries. Although no β stimulatory effects were
observed, it was suggested by the authors that this may have been due to species difference,
disease state (hypertension), or dosage regimen. As only one dose was used, no dose-dependent
effects could be determined.
Calapai et al. (1999) administered hydroethanolic extracts of Bitter Orange (standardized to 4%
or 6% synephrine), ranging from 2.5 to 20 mg/kg b.w./day, for 15 days, in Sprague-Dawley rats.
It was found that treatment resulted in reduced food intake and body weight gain, in a dosedependent manner. It was also found that rats given 20 mg/kg b.w./day developed significant
anomalies in ECG activity, including ventricular arrythmias and enlargements of the QRS
complex, by the tenth day of treatment. It was not indicated if ECG analysis was performed on
rats given lower doses.
Arbo et al. (2008) conducted 6 hour acute oral toxicity studies through administration by gavage
of C. aurantium unripe fruit extracts (2.5% p-synephrine, 300, 500, 1000, 2500, 3500, or 5000
mg/kg) or p-synephrine (150, 300, 450, 600, 800, 1000, or 2000 mg/kg) versus water control in
groups of 8 male albino CF1 mice. Reduction of locomotor activity persisting from 15 min. until
2 h post-treatment was seen at 1000-5000 mg/kg of the Bitter Orange extract and from 15 min.
until 1 hr post-treatment at 300 to 2000 mg/kg p-synephrine, which was confirmed in
spontaneous locomotor activity tests. Gasping (from 15 min. until 3-4 h) and salivation (from 15
min. until 30 min.) were seen at 150 mg/kg p-synephrine, and gasping, salivation, piloerection
(from 15 min. to 2 h), and exophthalmia (from 15 min. to 2 h) were seen at doses of 300 to 2000
mg/kg. There were no deaths and all the effects were reversible. Body weight gain over 14 days
following treatment was similar to control and at necropsy there were no alterations in the
removed organs. The authors speculated that the toxic effects observed seemed to be related to
adrenergic stimulation.
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In a subsequent subchronic toxicity study, Arbo et al. (2009) evaluated Bitter Orange extract and
p-synephrine in mice, treating groups of 9-10 male albino CF1 mice for 28 days with a
commercial C. aurantium dried extract (containing 7.5% synephrine) at 400, 2000, or 4000
mg/kg, or p-synephrine at 30 or 300 mg/kg, by oral gavage. There were no deaths, clinical signs
of toxicity, or changes in relative weights of organs in any of the treatment groups. There was no
significant change in body weight during treatment with any of the doses of Bitter Orange extract
but both doses of synephrine produced a significant decrease in body weight gain by the 28 day
measurement point.
Experience in Humans
Conditions of Use
Synephrine is a sympathomimetic (adrenergic agonist). It is used as a vasoconstrictor in
circulatory failure (Masten 2004). The tartrate salt is given orally to treat hypotension, and
ocularly (hydrochloride salt as well) as an ocular decongestant to constrict blood vessels in the
eye in order to reduce hyperaemia (Sweetman 2007).
Octopamine is used as a cardiotonic and to treat hypotension (Masten 2004).
Bitter Orange peel has GRAS status (FDA 2010a) and is often used in marmalade; the dried peel
is used in bouquet garni and for flavouring certain Belgian white beers, such as Orange Muscat
(Facciola 1998).
In Traditional Chinese Medicine (TCM), there are two medicinal materials, zhi qiao prepared
from the mature but still green Bitter Orange fruit peel collected in July and zhi shi prepared
from the immature fruit collected in May or June. They are both used to treat the TCM condition
of qi stagnation. With respect to Western diagnoses, both are added to multiple ingredient
formulas to treat indigestion, abdominal distension, tenesmus (urgent feeling of need and painful
straining to defecate or urinate, but that is not effective) distention and full sensation in the chest
and epigastric region of the body (Blumenthal 2004-2005). In contemporary use in China, it is
injected for the treatment of toxic shock and anaphylactic shock, weak heart conditions and
cardiac exhaustion. The peel is also used in TCM (Wichtl 2004), similarly to the whole dried
immature fruit (Wichtl 2004; Sweetman 2007).
Bitter Orange peel from ripe (Wichtl 2004; Council of Europe 2010) or either ripe or unripe fruit
(Fugh-Berman and Myers 2004) is used in modern herbalism and in the Eclectic medical
movement (Blumenthal 2004-2005) as a bitter aromatic digestive tonic to stimulate secretion of
gastric juice and the appetite in gastric hypoacidity disorders and as a flavouring agent for other
medicines.
Bitter orange peel is also used in South American folk medicine to treat anxiety, insomnia, and
as an anticonvulsant (Carvalho-Freitas and Costa 2002).
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In dietary supplements and natural health products, Bitter Orange peel and its extracts are used
orally for weight loss, increasing lean body mass, body building, improving athletic
performance, nasal congestion, allergic rhinitis, and chronic fatigue syndrome (NMCD 2011).
Bitter Orange extracts are often standardized for its synephrine content for thermogenic action
(Costa et al. 2011).
Dose Response
Ephedrine and Caffeine
Since Bitter Orange extracts, synephrine and octopamine have been investigated so much as
substitutes for Ephedra and ephedrine, the clinical evidence for Ephedra or ephedrine with
caffeine, for weight loss and athletic performance, will be briefly summarized to provide context.
Ephedrine combined with methylxanthines has been used in the treatment of asthma for decades.
A Danish physician noted weight loss in his patients on this regimen. The combination of 200
mg caffeine and 20 mg ephedrine three times per day was subsequently approved and marketed
for more than 10 years as a prescription medication for weight loss in Denmark (Bray and
Greenway 2007). Human clinical trials of ephedrine and caffeine for weight loss have been
reviewed by Bray and Greenway (1999) and Schekelle et al. (2003). Key findings were that none
of the weight loss trials assessed a duration of greater than 6 months, that weight loss in
comparison to placebo for the combination of ephedrine plus caffeine was 1.0 (CI95% 0.4-1.3)
kg/month, and safety data from 50 trials yielded an estimate of 2.2- to 3.6-fold increases in the
odds of psychiatric, autonomic, or gastrointestinal symptoms, and heart palpitations (Shekelle et
al. 2003).
Since those reviews were published, there have been a couple of clinical trials and an
observational study involving more than six months exposure to ephedrine plus caffeine.
Greenway et al. (2004) enrolled 12 healthy male and female adult subjects in a pilot study to
assess the effect of a multiple-ingredient product containing Ephedra (12 mg ephedrine), kola
and tea extracts (35 mg caffeine total), plus various other herbs and minerals, at a dose of 2 pills
on an empty stomach, on resting metabolic rate: 8% higher in treatment than control. Next, those
12 plus 28 more subjects were enrolled for a placebo-controlled trial of three months at the same
dose of product providing 24 mg ephedrine and 70 mg caffeine per day: weight loss at 12 weeks
was significant at 3.5 ± 0.6 kg with treatment vs. 0.8 ± 0.5 kg with placebo and fat loss was also
significant 7.9 ± 2.9% vs. 1.9 ± 1.1% and adrenergic symptoms from treatment including blood
pressure did not exceed placebo although 5 patients lost to follow-up could have failed to return
because of adrenergic symptoms. Finally, there was an open-label phase for 6 months: after a
total of 6 months treatment those in the treatment arm of the second phase of the study had lost
7.8 ± 1.9% of their body weight and those from the placebo arm had lost 7.3 ± 1.9%. The authors
noted that weight loss reached a plateau after 6 months of treatment and there were no serious
adverse events or clinical signs of toxicity.
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Hackman et al. (2006) conducted a 9-month trial of a multiple-ingredient dietary supplement
containing Ephedra herb extract (500 mg containing 40 mg ephedrine alkaloids), guarana extract
(550 mg containing 100 mg caffeine), plus other herbs, amino acids, fatty acids, plant extracts
and isolates, vitamins and minerals. Of 61 obese (BMI 29-37 kg/m2) but otherwise healthy (e.g.
hypertension excluded), pre-menopausal women enrolled, 41 completed the study. The treatment
group lost significantly more body weight (-7.18 kg) and body fat (-5.33 kg) than the controls (2.25 and -0.99 kg respectively), and showed significant declines in heart rate, serum cholesterol,
triglycerides, cholesterol to high-density lipoprotein ratio, glucose , fasting insulin, and leptin.
Blood pressure, electocardiograms, and other clinical chemistry, blood histology and urinalysis
results were similar to controls. Adverse effects reported as minor included dry mouth, insomnia,
nervousness and palpitations. The authors concluded that a supplement containing a low potency
ephedra/caffeine mixture could be used safely and effectively for loss of weight and body fat
under physician supervision.
Hallas et al. (2008) conducted a controlled observational study (registry-based case-crossover
study design) of data on 257,364 Danish patients prescribed an ephedrine (20 mg) and caffeine
(200 mg) combination product (Letigen), 1-3 tablets per day, for weight loss, over the period
from 1995 until 2002 when its marketing was suspended after reports suggesting a safety
problem. They found that under physician supervision, use of this specific quality-controlled
pharmaceutical ephedrine/caffeine product was not associated with adverse cardiovascular
outcomes over a wide range of patient subgroups, different cardiovascular outcomes (death
outside hospital, myocardial infarction, and stroke were the composite endpoint), different
assumptions about exposure, and different utilization patterns. There was nothing in the casecontrol analysis to suggest a delayed effect with continuous exposure e.g. mediated through a
hypertensive effect, or an increased risk among naive users or users with large cumulative doses.
The authors noted the implication that spontaneous reporting of adverse effects can “snowball”
where a product has acquired a poor reputation that generates new adverse reports.
Clinical trials of an ephedrine 20 mg/caffeine 200 mg combination observed side effects of
increased systolic blood pressure, tremor, insomnia and dizziness that were transient and after 8
weeks of treatment had reached placebo levels (Astrup et al. 1992, 1995; Astrup and Toubro
1993). A possible mechanism for this lack of significant adverse effects under physician
supervision is that caffeine combined with ephedrine stimulates both α- and β-ARs. The α-, β1and some of the β2-ARs down-regulate with time, while the β3- and some of the β2-ARs do not.
This allows ephedrine with caffeine to become a selective β2/β3-AR agonist over time as the
tremor, tachycardia, and nervousness lessen or disappear (Bray and Greenway 1999).
Synephrine
Despite the reported hypertensive effect of synephrine when used at doses of 100-150 mg, three
times daily, to treat hypotension (Sweetman 2007), and the evidence from animal-based models,
there is controversy in the literature as to whether or not synephrine from C. aurantium extracts,
used in amounts typically found in marketed weight-loss products, elicits hemodynamic
responses on its own.
Penzak et al. (2001) reported no effects on hemodynamic measures (systolic, diastolic blood
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pressure, mean arterial pressure, heart rate) in normotensive healthy adults (n=12) who were
nonsmokers, non-hypertensive, not on concomitant medication (prescription or otherwise) or
contraceptives in a two-way crossover open label study design following an acute dose of Seville
(sour) orange juice. Half the volunteers ingested a single dose of Seville orange juice (freshly
squeezed juice, 8 ounces/ 236.56 mL, providing 26 mg synephrine), while the other half ingested
water.
Bui et al. (2005) reported increases in systolic blood pressure and heart rate for at least 6 hours,
versus placebo, in healthy adults, following a single dose of 900 mg of C. aurantium extract
standardized to 6% synephrine (~54 mg). In contrast, using the same product, Min et al. (2005)
found no hemodynamic effect associated with a single dose of 900 mg of C. aurantium extract,
standardized to 6% synephrine, in healthy adults. Gougeon et al. (2005) found no hemodynamic
effect associated with a single dose of C. aurantium extract providing 26 mg of synephrine, in
healthy and overweight adults. Major limitations to these studies are that they all included
measurements after a single dose, so long-term effects cannot be extrapolated, and the study
populations are all healthy (even if overweight) normotensive individuals. Therefore, possible
responses in a hypertensive population are unknown. In addition, a placebo group was not
included in the study by Gougeon et al. (2005).
Shara et al. (cited in Stohs and Shara 2011) conducted a randomized, placebo-controlled doubleblind crossover study involving 16 healthy subjects administered one capsule of 50 mg psynephrine or placebo daily for 14 days. Blood pressure, heart rate, and electrocardiograms were
determined at 30 min., 60 min., 90 min, 2 h, 4 h, 6 h, 8 h, and then after one week and two
weeks. There was no significant effect on blood pressure or heart rate and there were no
cardiovascular abnormalities.
Stohs et al. (2011b) assessed the thermogenic effects of p-synephrine alone (Advantra Z
providing 50 mg of synephrine) and in combination with the flavonoids hesperidin and naringin
(0 mg + 600 mg; 100 mg + 600 mg; 1,000 mg + 600 mg, respectively) in a pilot double-blinded,
randomized, placebo-controlled trial with 10 healthy subjects/group. Resting metabolic rate
(RMR) , blood pressure and heart rate were measured and subjects’ self-reported mood/energy
levels were recorded while resting, at baseline and 45 min. and 75 min. after treatment. The
placebo group had a small decrease in RMR as anticipated due to continued fasting, while all
treatment groups showed an increase in RMR statistically greater than placebo, with a maximal
response vs. placebo of +183 kcal in group 4 (synephrine 50 mg, hesperidin 100 mg, naringin
600 mg). A dose of 1,000 mg hesperidin produced a much less than optimal increase in RMR.
No increases in systolic or diastolic blood pressure or heart rate were observed. There were no
significant effects relative to placebo in the self-reported symptoms including energy level,
concentration or adverse reactions.
Caffeine
Caffeine levels peak (Tmax) 30-120 min. after oral intake and the half-life (T1/2) is 3-6 h. Blood
pressure changes occur within 30 min. of ingestion, peak in 1-2 h, and may persist for more than
4 h. Changes are usually in the range of an increase of 3-15 mm Hg systolic and 4-13 mm Hg
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diastolic. Caffeine tolerance diminishes the acute effect of caffeine on blood pressure.
Hypertensive individuals are more susceptible to blood pressure changes (Mort and Kruse 2008).
Synephrine + Caffeine
Haller et al. (2005) conducted a randomized, double-blind, 3-arm crossover study in 10 healthy
adults with Xenadrine EFX, a multiple-ingredient product including vitamins C, B6 and B5,
magnesium, L-tyrosine, acetyl-L-tyrosine, green tea extract, cocoa extract (containing
phenylethylamine, tyramine and theobromine), yerba mate, d-methionine, ginger root, 3,3’,4’,57-pentahydroxyflavone, 3,3’,4’,7-tetrahydroxyflavone, 2-dimethylaminoethanol, grape seed
extract, and Bitter Orange extract (providing synephrine, n-methyl-tyramine, hordenine,
octopamine and tyramine). Some ingredients are sources of caffeine, and other ingredients are
relevant to sympathetic nervous activity, e.g., phenylethylamine is a chemical precursor for other
sympathomimetic agents (Katzung 2001); parenteral administration of tyramine has an indirect
sympathomimetic action by causing a release of stored catecholamines (Katzung 2001); and
hordenine has positive inotropic activity (Hoffman 2003). Xenadrine EFX was chemically
analyzed and found to contain per 2-capsule dose 5.5 mg synephrine, 5.7 mg octopamine, and
239.2 mg caffeine, in addition to other herbal extracts and isolates, vitamins and minerals, with
Advantra Z analyzed to provide 46.9 mg synephrine per 3 tablet dose, versus placebo. With
respect to pharmacokinetics, synephrine’s Tmax was 75 min., T1/2 was 3.1 ± 2.2 h, Cmax was 2.85
± 0.86 ng/mL. Caffeine’s Tmax was 90 min., T1/2 was 7.8 ± 3.1 h, Cmax was 5.1 ± 1.3 µg/mL.
Octopamine’s pharmacokinetics could not be measured since 99% of the plasma samples
measured were below the limit of quantitation of 0.2 ng/mL. Xenadrine EFX significantly raised
mean systolic (+9.6 ± 6.2 mm Hg) and diastolic (+9.1 ± 7.8 mm HG) blood pressure with a
maximal increase 2 h after ingestion. Heart rate was significantly elevated compared with
placebo only at the 6 hour time point after dosing. Advantra Z did not raise systolic or diastolic
blood pressure but showed a similar increase in heart rate at the 6 h point. However, at 8 h posttreatment, placebo and both treatment groups had similar elevated levels of heart rate but these
were all well within the normal range of heart rate increase associated with normal activities
undertaken by healthy adults (McGuffin 2007). Haller and Benowitz (2007) replied that the
mean peak heart rate increases observed with bitter orange alone or the bitter orange-pluscaffeine were approximately 2-fold higher than the heart rate increase observed with placebo and
was a statistically significant difference seen while subjects were at rest. Stohs et al. (2011a)
noted that this increase in heart rate does not coincide with the pharmacokinetics of p-synephrine
but with the thermic effect of food. Whatever the cause, the maximum difference of 16
beats/min. with the Xenadrine EFX treatment may not be clinically significant.
Hoffman et al. (2006) examined the effects of JavaFitTM, which is a source of synephrine and
caffeine, in healthy, physically active subjects, who were all regular coffee drinkers, following a
single dose, providing 450 mg of caffeine, 1200 mg of Garcinia cambogia (standardized to 50%
hydroxycitric acid), 360 mg of C. aurantium extract (standardized to 6% synephrine alkaloids =
21.6 mg), and 225 µg of chromium polynicotinate. The control group was a placebo group which
included a standardized coffee drink. The study included a cross-over design, for an effective
sample size of 10 per group. The authors reported a statistically significant increase in systolic
blood pressure in the JavaFitTM group, versus coffee alone.
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Fugh-Berman and Myers (2004) have suggested that overweight individuals may be particularly
susceptible to the effects of synephrine + caffeine: overweight individuals are commonly
hypertensive and may react differently to vasopressors.
On the other hand, there is evidence that supports the absence of cardiovascular responses to
products providing synephrine and caffeine or, possibly, that tolerance may develop to the
hemodynamic effects, over time as were observed for ephedrine/caffeine. Although no data are
provided, Colker et al. (1999) reported no significant effects on blood pressure and heart rate
(not the primary end points) in a 6-week double-blind, randomized, placebo-controlled trial in
subjects (n = 9) who received 975 mg C. aurantium extract (6% synephrine = 58.5 mg), caffeine
528 mg, and St. John’s Wort 900 mg/day. Acute hemodynamic effects could have been missed
since subjects were evaluated only at baseline, week 3 and week 6.
Greenway et al. (2006), in an 8-week pilot study, randomized eight subjects to a multicomponent supplement (18 mg synephrine/ day + ≥ 400 mg caffeine) or placebo and also found
no effects on blood pressure and heart rate (measured at baseline, 2, 4 and 8 weeks). However,
the authors confused m-synephrine/phenylephrine with p-synephrine as the active constituent of
C. aurantium, so it is not clear what was actually tested in this clinical trial.
Zenk et al. (2005) examined the effects of the multiple-ingredient herbal supplement Lean
System 7 on metabolic rate and other hemodynamic parameters, in generally healthy, but
overweight adults (n=24), versus placebo (n=23). The supplement provided, daily, 102 mg of 3acetyl-7-oxo-dehydroepiandrosterone, 600 mg of C. aurantium extract (36 mg of synephrine),
300 mg of Coleus forskohlii extract (60 mg forskolin), 1000 mg of yerba mate and ~1400 mg of
guarana (308 mg of caffeine). While persons with “uncontrolled hypertension” were excluded,
the mean baseline blood pressures (supplement group: systolic blood pressure of 125.8 ± 13.7
mm Hg, diastolic blood pressure of 74.3 ± 10.9 mm Hg; placebo group: SBP of 128.8 ± 17.9 mm
Hg, DBP of 78.6 ± 10.4 mm Hg) suggest that at least some subjects were hypertensive. The
treatments were administered over a period of 8 weeks. There were no statistically significant
differences in the changes in blood pressure or heart rate between groups. With respect to
adverse events, the authors comment that there were no differences in the number of adverse
events experience between groups, but the supplement group experienced 2 incidences of nausea
and 1 incidence of urticaria that were considered possibly related to treatment. While this study
does tend to support the safety of synephrine + caffeine in an overweight population, it is still
limited by the relatively small study population, and the relatively short duration of study. The
results cannot be used to justify long-term safety.
Sale et al. (2006) examined the acute effects of ingestion of a commercial formula containing
extracts of Bitter Orange (synephrine 6 mg/dose), green tea and guarana (caffeine 150 mg/dose,
catechin polyphenols 150 mg/dose) on the metabolic rate and substrate utilization in overweight,
adult males (n=5 per treatment or placebo arm) at rest and during treadmill walking. Although
systolic and diastolic blood pressure were consistently slightly higher in the treatment than in the
placebo group, the differences were not significant for risks or benefits in this very small singledose study.
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Haller et al. (2008) studied the effects of Ripped Fuel Extreme Cut®, in healthy adults, after
single dose of product, providing 21 mg of synephrine (from C. aurantium), 303.8 of caffeine
(from green tea leaf, guarana seed and caffeine), 40 mg of niacin, 150 µg of biotin, 12 mg of
pantothenic acid, and undeclared amounts of ginger root extract, cocoa seed extract, cayenne
fruit, quercetin, wasabi extract, naringin complex, white willow bark extract, l-tyrosine, catuaba
bark, and citrus bioflavonoids. The study was three-arm (test product + moderate-intensity
exercise vs. test product + rest vs. placebo + exercise), double-blind, placebo-controlled
crossover study. Diastolic blood pressure was statistically significantly increased in the test
product + exercise group vs. placebo + exercise group. In these same groups, systolic blood
pressure was reportedly elevated, but not to a statistically significant degree (P < 0.077).
Recently, Seifert et al. (2011) examined the acute hemodynamic effects of a supplement in 23
mildly overweight (overall BMI 26.6 ± 3.8) subjects, three of whom were pre-existing
hypertensives (systolic blood pressure > 140 mm Hg). The study involved a placebo-controlled
crossover design. Each product capsule provided 13 mg of synephrine (from a C. aurantium
extract), 176 mg of caffeine, 55.5 mg of a green tea extract, 1 mg of bee pollen, 1 mg of white
willow bark powder, 2 mg of Panax ginseng root, 2 mg of Garcinia cambogia extract and 0.15
µg of vanadium. Three capsules were taken on the day prior to examination, and the last capsule
after a 12-hour overnight fast. Following the last dose, measurements were taken after a 60minute relaxation period. There were no reported differences in heart rate, blood pressure or
respiratory exchange ratio, in the treatment vs. placebo groups. A major limitation to this study is
that the last dose was administered after a 12-hour fast. Given the clearance of synephrine and
caffeine (the authors estimated 60 min. to maximal blood levels), the effects of the product, or
lack thereof, should only be attributed to the last single dose of the product, and not all 4 doses
over the preceeding 24 hours. Another limitation is that this study was done at rest, thus the
effects the stimulant ingredients may have had in an excited state (e.g., such as when exercising)
would not have been seen.
Adverse Reaction Reports
Case reports do not demonstrate causation or association but repeated co-occurrences can be
considered signals used to generate hypotheses and potentially, to raise safety concerns.
Public and regulator concerns over reports of serious adverse reactions to products containing
Citrus aurantium were triggered by an April 11, 2004, article in the New York Times citing an
unidentified U.S. Food and Drug Agency spokesperson that there had been 85 adverse reactions
and 7 deaths. By June of 2004 the FDA reports rose to 147 cases and by July 169 cases.
However, subsequent investigations into these reports revealed that there were many apparent
duplicates and very incomplete reports, at least 82 reports did not identify a Bitter Orange
ingredient in the associated product but were products with ephedrine-containing ingredients, 40
were cases in which not only Bitter Orange but also caffeine was present, and only one adverse
reaction report involved a product in which the only ingredient was Bitter Orange. In that case,
there were three separate herbal formulas prescribed by a Chinese herbalist, not a commercial
product, and there were several concomitant prescription drugs that may have contributed to the
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adverse effects (McGuffin 2004, 2006a). FDA’s Center for Food Safety and Applied Nutrition
made some corrections to its adverse event reporting procedures for bitter orange following this
miscalculation of the number of AERs tied to the ingredient (Anonymous 2004).
Stohs (2010a) reviewed 22 adverse reaction reports received by the FDA from April 2004 to
October 2009 and the 10 clinical case reports from the literature involving adverse events
associated with products labelled as containing Bitter Orange extracts or p-synephrine. Reported
adverse events included acute lateral-wall myocardial infarction, exercise-induced syncope
associated with QT prolongation, ischemic stroke, variant angina, ischemic colitis, coronary
spasm and thrombosis, vasospasm and stroke, ST segment elevation myocardial infarction,
ventricular fibrillation, and a suggestion of masking of bradycardia and hypotension while
exacerbating weight loss in an indivual with anorexia nervosa. Stohs’ conclusions were that “All
products involved in these reports were poly-herbal and poly-alkaloidal in composition. The
conclusion that BOE and p-synephrine are responsible for adverse events presented in these
reports is unjustified, based on the presence of confounding factors, the paucity of detailed
information in many reports, current knowledge of the pharmacokinetic and adrenoreceptor
binding properties of p-synephrine, the high probability of concurrent but independent events,
knowledge of dose–response relationships, and the widespread use of BOE containing
supplements and p-synephrine containing juice and food products.”
Stohs (2010a), Stohs and Shara (2011), Stohs and Preuss (2011) and Stohs et al. (2011a) have
noted that many of the products linked by the various authors to these case reports contained 5 to
12 alkaloidal and protoalkaloidal ingredients in addition to p-synephrine, including yohimbine
and ephedrine, plus large doses of caffeine. Underlying conditions that may have contributed to
the adverse events included morbid obesity, asthma, diabetes, hypertension, hyperlipidemia,
heart attack, stroke, pneumonia, alcoholism, drug abuse, depression, anxiety, and nicotine use, as
well as dehydration during use.
Rossato et al. (2011) have also recently reviewed the evidence for safety of synephrine. Stohs
(2011) has criticized this review for its lack of clarity on p- versus m-synephrine as the active
consituent of Citrus aurantium and consequent relevance to assessment of adverse reaction
reports, and for other weaknesses. Rossato (2011) replied to point out that adulteration of dietary
supplements with m-synephrine has been reported by several authors so their discussion of this
positional isomer is relevant.
Inchiosa (2011) has also recently reviewed the safety and efficacy of sympathomimetic agents
for weight loss, including brief sections on synephrine and ephedrine.
Keeping in mind the comments of Stohs and colleagues, cited above, and the review by
McGuffin, regarding the reliability of the adverse reaction case reports in the literature and from
the FDA, the literature case reports and Health Canada’s domestic adverse reaction reports are
nevertheless summarized below to present as complete a picture as possible of the information
available upon which to base an assessment of the potential for synephrine alone or in
combination with other substances to present risks to health.
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Cardiovascular Adverse Reaction Case Reports from the Literature
A case report of myocardial infarct due to coronary spasm was reported in a 28-year-old male
who was a heavy smoker, and abusing oxedrine (synephrine) tablets; the dose of synephrine was
not disclosed (Keogh and Baron 1985). A case of unremitting tachycardia was reported in a 55year-old woman, following a single dose of Bitter Orange for weight loss (500 mg Bitter Orange,
standardized to 6% synephrine, providing 30 mg synephrine); the individual was also taking
concomitant thyroxine (Firenzuoli et al. 2005). This case report suggests that even at doses of 30
mg synephrine, concomitant use with thyroxine may predispose certain individuals to adverse
health effects.
In a case study involving Xenadrine EFX, Nasir et al. (2004) reported the possibility of the
product being associated with exercise-induced syncope, associated with QT prolongation. A 22year old woman had taken Xenadrine EFX for 1 year, stopped for 3 months prior to the incident,
and resumed her routine the day before the incident. She reported taking 1 tablet 45 minutes
before running. Near the end of a 3.5-mile run, she reported feeling light-headed, sensing a rapid
heart rhythm and then losing consciousness and falling. Examination in hospital revealed sinus
tachycardia with QT prolongation, which normalized within 4 hours. A heart murmur was
identified on admission, but further investigation revealed no evidence of valvular heart disease,
normal ventricle size normal systolic function, normal wall thickness and no wall abnormalities.
The following day, an exercise stress-test was administered and no cardiac abnormalities were
observed. However, certain doubts of a causal association were raised by Hamilton (2005), who
pointed out that the patient’s anion gap acidosis and ketosis are consistent with starvation, which
may have contributed to the adverse event.
Gray and Woolf (2005) suggested that the adrenergic agonist properties of a C. aurantium (325
mg standardized to 6% synephrine alkaloids) + guarana (800 mg standardized to 22% caffeine)
supplement may have masked bradycardia and hypotension while exacerbating weight loss in a
16-year-old woman with anorexia nervosa.
Bouchard et al. (2005) reported the occurrence of ischemic stroke, presumably of vasospastic
origin, in a 38-year-old male who smoked 5 cigarettes per day but with no other major risk
factors for atherosclerotic disease and no concomitant medications, who consumed 1-2 capsules
of Stacker 2 Ephedra-free dietary supplement for one week prior to presentation. This multipleingredient product contains 6 mg synephrine and 200 mg caffeine per capsule. The authors
concluded that the stroke was “probably secondary to synephrine.”
A case of possible myocardial infarction (MI) was reported in a 55-year-old woman following
use of a Bitter Orange containing supplement (Nykamp et al. 2004). The supplement contained
300 mg Bitter Orange (dose of synephrine not disclosed), in addition to 250 mg carnitine, 400 µg
chromium, 300 mg Citramax® (hydroxycitric acid, from Garcinia cambogia), 250 mg chitosan,
and sources of caffeine including guarana seed extract (250 mg) and green leaf tea extract (30
mg). The amount of synephrine was not specified. Although the patient did not have an
underlying history of hypertension, coronary artery disease, or hyperlipidemia, she did have a
lesion in the left main coronary artery and had a history of 1.5 pack/day smoking habit.
Synephrine was said to be possibly associated with this event.
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A case report of variant angina involving the right coronary artery was reported in a 57-year-old
male, following use of a Bitter Orange- and green tea-containing product for 35 days (1 tablet
twice daily; 125 mg/tablet of a Bitter Orange and green tea proprietary blend) (Gange et al.
2006a). No previous adverse reactions were reported by the patient during prior use of the
product, and the product was last taken 17 hours prior to the AR. The patient did have a history
of hypertriglyceridemia, gastro esophageal reflux disease, and a 60-pack per year smoking
history, but had quit 7 years previously. He denied illicit drug use, but did consume 3-4 alcoholic
drinks per day. Medications included fenofibrate, omeprazole, aspirin, a multi-vitamin, vitamin
B complex and vitamin E. A temporal link between the product and the adverse reaction was
proposed by the authors; however, due to the gap in time between the last time the product was
taken (17 hours previously), and the patient experiencing further chest pain 4 months after
discontinuation of the product, the cardiovascular effects may not have been product-related.
McGuffin (2006b) has criticized this report for attributing a causal relationship to the Bitter
Orange peel extract (5% synephrine) which together with green tea leaf extract constituted 125
mg of a “Leptiplex” mix (thus perhaps 3 mg synephrine), when the product, CortiSlim, also
contained chromium polynicotinate, vanadyl sulfate, magnolia bark extract, L-theanine, bamboo
leaf extract, beta-sitosterol, calcium and vitamin C, and there were concomitant medications and
regular alcohol consumption. Gange et al. replied (2006b) that the hypertension could be
attributed to the subjects underlying factors of alcohol intake and obesity, but maintained that the
dietary supplement may have exacerbated the variant angina.
A case report of acute myocardial infarct (MI) was reported in a bodybuilder, following use of a
supplement containing synephrine, octopamine, tyramine and caffeine (Smedema and Müller
2008). The 39-year-old bodybuilder presented with new-onset angina pectoris and vegetative
symptoms during a bodybuilding competition. The individual did not have any previous medical
history or cardiovascular risk factors including atherosclerosis plaque, and denied using anabolic
steroids. He had been taking the product for ‘several years’ , and in the 3 months preceding the
competition, had taken a daily dose of the product providing 40 mg synephrine, 400 mg caffeine,
and unknown levels of octopamine and tyramine; the product also contained St. John’s Wort.
The individual had also restricted fluid intake, and increased carbohydrate intake prior to the
competition. The authors concluded that the MI was probably caused by a coronary spasm and
thrombosis due to use of the product, in combination with dehydration and impaired renal
function.
A case report of vasospasm and stroke was reported in a previously healthy 36-year-old woman,
following the use of a synephrine- and caffeine-containing supplement (Xenadrine EFX) for
purposes of weight loss ‘for a few months’ leading up to the AR (Holmes and Tavee 2008). The
individual experienced right upper extremity weakness, difficulty speaking, in addition to facial
droop and severe headache, 1 hour later. The neurological deficits resolved a few hours later,
however, the headache persisted. There was no previous history of migraine headache,
thrombophilia, hyperlipidemia, tobacco use, or oral contraceptive use. The only concomitant
health product was an iron supplement. There was no pertinent medical history, or abnormal
results from general and neurological exams, except for mild flattening of the right nasolabial
fold. An MRI and MRA (magnetic resonance angiography) revealed a left middle cerebral artery
infarct, consistent with a vasospasm. All other medical and laboratory exams were normal. Two
weeks after discontinuation of the supplement, and intervention with aspirin, there was resolution
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of the vasospasm, and facial weakness completely resolved after 1 month. The authors suggested
that the vasospasm and stroke was related to the use of the synephrine-containing product, given
the lack of stroke risk factors, normal inflammatory market profile and resolution of the
vasospasm after the supplement was discontinued.
Stephensen and Sarlay (2009) reported a case of ventricular fibrillation that they associated with
use of a dietary supplement containing synephrine. However, the product, Lipodrene, has
multiple other ingredients that may have contributed to the adverse reaction (Stohs 2010b).
Thomas et al. (2009) attributed a case of ST-segment-elevation myocardial infarction (STEMI)
in a previously healthy 24 year old man to consumption of a dietary supplement, Nutrex Lip-6X
and its constituent, synephrine. Stohs (2010c) pointed out that this multi-ingredient product
contains at least 7 alkaloids and that the evidence does not support pharmacological properties of
synephrine being similar to ephedrine. Thomas et al. (2010) replied that they agreed it is not
possible to know with certainty the precise agent or synergistic interaction that caused the
myocardial infarction in the subject but they still believed synephrine was the most likely cause.
Non-cardiovascular Adverse Reaction Case Reports from the Literature
Although Bitter Orange/synephrine-containing products have been predominantly associated
with adverse cardiovascular reactions, a case report of ischemic colitis, as well as a case of
rhabdomyolysis have been associated with use of two multi-ingredient Bitter Orange-containing
products.
A case report of ischemic colitis was reported in a 52-year-old woman, following the use of a
Bitter Orange-containing supplement for weight loss for 1 week leading up to the adverse
reaction (Sultan et al. 2006). The product did contain other ingredients, including, per capsule,
300 mg Garcinia cambogia, 250 mg L-Carnitine, 250 mg Chitosan, and 200 µg chromium
arginate (3 capsules per dose recommended); however, the authors posited that the other
ingredients did not mediate these effects, and that the adverse event was due to synephrine’s
vasoconstrictive effects resulting in decreased portal tributary blood flow, which has been
observed with synephrine in a rat model of portal hypertension (Huang et al. 2001).
A case of rhabdomyolysis was reported in a previously healthy obese 22-year-old male with
sickle cell anaemia, following his use of a synephrine- and caffeine-containing dietary
supplement (Burke et al. 2007). The patient presented with fatigue, light-headedness and
myalgia, which developed during an exercise test, and was diagnosed with exercise-induced
rhabdomyolysis with heat exhaustion. Several weeks later, the patient resumed the exercise tests
without medical clearance, and experienced a second episode of rhabdomyolysis and heat
exhaustion while running. He presented with hypotension, tachycardia, tachypnea, and myalgia.
The individual also experienced muscle hypoxia and ischemia. The patient further developed
hypovolemic shock, respiratory failure and acute renal failure. Despite extensive medical
intervention, the patient sustained permanent bilateral sensory and motor neurological deficits in
both distal lower extremities. Following the second episode of rhabdomyolysis, the patient
admitted to the use of a synephrine and caffeine-containing supplement twice daily during the
last 3 months leading up to the AR; the product also contained yohimbine HCl. Reports of
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rhabdomyolysis have been associated with large doses of caffeine; the contribution of synephrine
in this case report is unclear, as no other reports of rhabdomyolysis have been documented to be
associated with synephrine. Confounders in this case report include the sickle cell anaemia trait
and intense physical exercise in a warm climate.
Canadian Domestic Adverse Reaction Case Reports
From January 1, 1998, to March 31, 2008, Health Canada received 61 domestic case reports of
adverse reactions suspected to be associated with Bitter Orange (Citrus aurantium)- and
synephrine-containing natural health products. At the time of the initial causality assessments,
only 51 reports had been entered into the Canada Vigilance database. Of these 51 reported cases,
44 were assessed for causality; 18 out of the 25 adverse reactions reported from 1998–2004 were
reviewed based on suspected cardiovascular adverse reactions. Post-2004, all adverse reaction
reports associated with Bitter Orange/synephrine were reviewed.
Of the 44 analyzed reports:
 Bitter orange/synephrine was noted to be typically part of a multi-ingredient formulation,
most often for the indication of weight loss;
 35 of the 44 case reports were cardiovascular in nature, of which 27 were classified as
“serious”. An additional report of “chest pain” was assessed as “serious”; however, its
cardiovascular origin was not assessable;
 2 out of the 44 case reports had “death” as an outcome, 20 cases had “recovered without
sequelae”; 2 cases “recovered with sequelae”; 1 “not yet recovered”, and 19 cases had
outcome as “unknown”;
 The 2 fatal case reports involved a 21 year-old male and a 29 year-old female. Both of these
cases were associated with Bitter Orange/synephrine-containing products that also contained
Ephedra/ephedrine and caffeine. Causality for these cases has been assigned “possible” for
synephrine’s contribution;
 3 of the 44 cases involved misuse (abuse or suicidal attempt);
 10 of the 44 cases had Bitter Orange/synephrine with concomitant Ephedra/ephedrine and
caffeine ingredients. Causality for these cases was assigned as “possible” for synephrine’s
contribution to the adverse events;
 33 of the 44 cases had Bitter Orange/synephrine with concomitant caffeine or sources of
caffeine (without Ephedra/ephedrine) in the suspect product(s). Causality for these cases has
been assigned as follows: 30 “possible”, 1 “probable”, 1 “unassessible”, 1 “unlikely” for
synephrine’s contribution to the adverse events;
 The causality for the role of synephrine was “possible” in most case reports. It was not
“probable”, since almost all of the suspect products contained Bitter Orange/synephrine in
combination with sources of caffeine;
 Only one case can be identified as having synephrine without concomitant
Ephedra/ephedrine alkaloids or caffeine. Causality for this case has been assigned as
“probable” for synephrine’s contribution to the adverse events. This case involved a 43 year
old patient (gender not specified) who developed tachycardia and dyspnea after having
ingested 4 doses of Slim Essentials Weight Loss Formula over a period of 3 days. The patient
required 3 days of hospitalization. The clinical events in this case had a positive temporal
relationship, and positive dechallenge. The patient had no prior history of coronary artery
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


disease, no concomitant medications and the laboratory and thallium test were reported
normal in hospital;
In 14 of the 44 cases, the standardized level of synephrine in the Bitter Orange products was
specified but the actual dosage of Bitter Orange was not reported, so the dose of synephrine
cannot be calculated;
The nature of the cardiovascular adverse reactions associated with Bitter Orange/synephrine
were variable: tachycardia, hypertension, syncope, breathing difficulty, chest pain,
ventricular fibrillation, cardiac arrest, and death. For Bitter Orange-containing NHPs, 46.2%
of reported reactions involved gastrointestinal disorders, followed by 42.3% nervous system
disorders, 34.6% general disorders and administration site conditions, and 30.8% cardiac
disorders;
In terms of demographics, as weight loss is the predominant indication of the suspect
products, the main at risk population are women (29 out of the 44 cases involved women, 14
involved men; in 1 report, gender was not specified), and young adults (19 cases involved
patients in the 20s; age ranged from 16-64 years old).
A recent search of the Canada Vigilance databases has indicated that there have been 5 new
adverse reaction case reports for products containing caffeine and synephrine (excluding
ephedra) have been identified since March 31, 2008. Only one of the adverse reactions is
cardiovascular in nature (chest pain), but this was associated with Slimming Coffee, which was
subject to a Public Warning on January 14, 2010, as it was adulterated with sibutramine. The
other four adverse reaction reports, all from multi-ingredient products, included: rhabdomyolysis
(CPK > 10,000) associated with Green Tea Fat Burner; seizure (new onset) associated with
Thermo-lean; increased liver function tests associated with Greens + and Xenadrine; and allergic
reaction associated with Happy Planet Shots-Energy and Glow. This recent search does not
provide additional information for cardiovascular risk assessment with respect to synephrinecontaining products.
Potential Citrus aurantium/Synephrine – Drug Interactions
Fugh-Berman and Myers (2004) cited a potential for drug interactions between Bitter Orange
and drugs based on the ability of C. aurantium juice to inhibit the key cytochrome P450 drug
metabolizing enzyme CYP3A4 in the intestinal wall. Bitter Orange juice was found to contain
furanocoumarins such as bergamottin at 5 µM/L and 6',7'-dihydroxybergamottin at 36 µM/L,
which are potent CYP3A4 inhibitors, and Bitter Orange juice did interact with the model
CYP3A4 substrate felodipine (Malhotra et al. 2001). C. aurantium has been shown in vitro to
inhibit CYP3A4 (Guo et al. 2001). However, comparing juice consumption with dietary
supplement use may not be appropriate, nor is directly relating effects from intravenous
administration to oral administration (Dentali 2005). Fugh-Berman and Myers (2005) replied to
Dentali that furanocoumarins are present in the rind and so would be expected to be found in rind
extracts. Phytochemical analysis of dietary supplements containing C. aurantium found no
detectable 6',7'-dihydroxybergamottin, probably due to the commercial method of extraction
with water in which these furanocoumarins are extremely poorly soluble, and an in vivo
assessment in 12 healthy volunteers treated for 28 days found no changes in the enzymes
CYP3A4, CYP1A2, CYP2E1 or CYP2D6 (Gurley et al. 2004). Therefore, in contrast to the
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juice, dietary supplement extracts of C. aurantium are not likely to cause any clinically
significant interaction with drugs through the cytochrome P450 system.
However, the physiological effects of Bitter Orange and its phenylpropanoid constituents may be
exacerbated by monoamine oxidase inhibitors (MAOIs), potentially causing hypertension.
Synephrine, as well as octopamine and tyramine, are MAO substrates (Suzuki et al. 1979;
Visentin et al. 2001). The mechanism depends on the mode of action of the sympathomimetic:
with a predominantly direct-acting sympathomimetic such as phenylephrine (subject to gut wall
metabolism by monoamine oxidase), MAOIs increase absorption (Elis et al. 1967); with indirectacting sympathomimetics, MAOIs increase the amount of NE stored in adrenergic nerve endings
(Sweetman 2007). Interactions may also occur with tricyclic antidepressants since they block the
inactivation of epinephrine and NE by uptake into the nerve endings and may increase their
effect; hypertension and arrhythmias may occur (Sweetman 2007).
Elevated thyroid hormone concentrations may enhance adrenoceptor sensitivity (Sweetman
2007). Larger doses of thyroid hormone may produce serious or even life-threatening
manifestations of toxicity when given in association with sympathomimetic amines (Genpharm
2005). Firenzuoli et al. (2005) reported unremitting tachycardia in a patient taking C. aurantium
(30 mg synephrine daily) and thyroxine; the tachycardia resolved upon de-challenge and recurred
upon re-challenge a month later. The arrhythmia again resolved upon discontinuation of Bitter
Orange. A report of cardiac arrest in a 29-year old woman taking a synephrine-containing
product and Synthroid was also received by Health Canada in 2002 (Health Canada 2007).
Exposure
Citrus fruit is the only potential dietary source of synephrine (Wheaton and Stewart 1970).
Frozen concentrated orange juice may contain up to 5% Bitter Orange juice by volume (FDA
2010b). Synephrine occurs naturally in citrus juices at concentrations of 2 mg/L in Meyer lemon,
11 mg/L in rough lemon, 20 mg/mL in sweet lemon, 15 to 30 mg/L in several varieties of sweet
orange juice, 27 to 43 mg/L in temple orange, 46 mg/L in the Orlando variety of tangelo, 50-52
mg/mL in Murcott orange, 58 mg/L in the Robinson variety of tangerine juice, 97 to 152 mg/L in
the Dancy variety of tangerine juice, 73 to 158 mg/L in Satsuma mandarin, and 280 mg/L in
Cleopatra mandarin orange juice. Synephrine is below quantification limits in common lemon,
lime, and grapefruit juices (Stewart and Wheaton 1964; Wheaton and Stewart 1965; Dragull et
al. 2008). The concentration of synephrine is highest in immature citrus fruits and decreases
proportionally with increasing diameter of the fruit as they mature (Hosoda et al. 1990).
A typical dose used in TCM, for example in the Jianpi Wan formulation is 1.25 g dry herb (peel)
per day (PPRC 2000) which at a concentration of ~0.25% of synephrine, would amount to 3.1
mg/day. The dose of dried fruit in decoctions ranges from 3-10 grams/day (Blumenthal 20042005).
In modern European herbal medicine, Bitter Orange peel is used at a dose of 4-6 g, 2-3 g in
tincture, and 1-2 g in extract (Blumenthal 1998).
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Bitter Orange extracts naturally contain up to 4% synephrine. Commercially available extracts
commonly contain 4%, 6%, 10% or ≥ 30% synephrine; some manufacturers boost the synephrine
content to 90-95% (Masten 2004; FDA 2005; NDPSC 2003).
Gregory (2007) found that of 36 dietary supplements marketed as “ephedra-free,” 32 (89%)
contained a methylxanthine such as caffeine or theobromine, 21 (58%) contained synephrine,
and 20 (56%) contained both a methylxanthine and synephrine. Avula et al. (2005) found that in
dietary supplements claiming to contain Citrus aurantium, there were significant differences in
their composition and that in 6 of the 8 products where the quantity of Bitter Orange herb or
extract was listed (85 to 900 mg), that quantity did not correlate with the content of synephrine
even though it was the major amine present. The highest concentration of synephrine seen was
18.62% and the lowest concentration was 0.073%. N-methyltyramine was detected in the range
of 0.13% to 0.16% in six of the products. Trace levels of octopamine were detected in four of the
products, traces of tyramine in two, and traces of hordenine in three.
NMCD (2011) lists 537 dietary supplements containing Bitter Orange but many of these are
cosmetics with orange oil and TCM products not relevant to this analysis. Of the weight loss or
body building tpes of dietary supplements, many avoid specifying the content of Bitter Orange,
synephrine, caffeine or other ingredients by listing a “proprietary blend” where ingredients are
named but not quantified. Where quantities were provided, the dose of Bitter Orange ranged
from 20 mg to 5500 mg, the dose of synephrine according to the labels ranged from 3 mg to 72
mg, and the dose of caffeine ranged from 16 mg to >1000 mg. Common ingredients that are
additional sources of caffeine included green tea, kola, guaraná, maté, and cacao, often
standardized to methylxanthines (caffeine, theophylline, theobromine). Some products contained
octopamine at 100 mg or 200 mg per dose. NMCD applied a blanket cautionary statement to all
Bitter Orange containing products, whether or not there was any evidence for the presence of
synephrine.
Products of this type investigated by Health Canada have generally contained a similar range of
active ingredients. The product providing the highest dosages seen so far is Thermonex, for
which the labelled maximum daily dose provides1000 mg anhydrous caffeine plus green tea
extract (1500 gm) and yerba maté (800 mg), 800 mg octopamine HCl, 80 mg synephrine, 200
mg naringin, 160 mg of the cardioactive alkaloid evodiamine, plus the thyroid action modulating
ingredients L-tyrosine (1200 mg), iodotyrosine (400 µg) and diiodotyrosine (400 µg). Health
Canada issued a Public Health Warning regarding this product in May of 2004 (Health Canada
2004).
Stohs (2010a) estimates that more than 100 million doses of products containing Bitter Orange
extract or p-synephrine have been consumed in the U.S. in the past 15 years.
Synephrine has been marketed as a drug under the name Oxedrine since 1927 (Haaz et al. 2006).
It is a sympathomimetic given as the tartrate in the treatment of hypotensive states in doses of
100 to 150 mg three times daily by mouth; it has also been given by subcutaneous,
intramuscular, or intravenous injection. Oxedrine is also used in eye drops as an ocular
decongestant, usually as the tartrate in a concentration of 0.5% in combination preparations. The
hydrochloride has also been used. Currently marketed single ingredient preparations include:
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Sympatol (Germany, Italy), Sympalept (Switzerland), Sympathomim (Hungary), Ocuton (Hong
Kong). Currently marketed multi-ingredient preparations include Dacrin and Pasuma-Dragees
(Austria), Dacryne, Dacryboraline, Polyfra, Posine, and Sedacollyre (France) (Pharmacopoeia
Site 2011). Oxedrine tartrate is not marketed in the United States or Canada. Note that Sympatol
is racemic p-synephrine tartrate in which the natural (-)-enantiomer of p-synephrine comprises
34.5% of the dose, i.e. 100 to 150 mg of Sympatol supplies 34.5 to 51.8 mg of (-)-p-synephrine
(Inchiosa 2011).
Risk Characterization and Classification
Citrus aurantium Peel
Based on the conditions of use in foods and traditional medicines, and the exposure from these
products which are readily available in the Canadian market, it is highly unlikely that the
botanical material, Bitter Orange peel, Citrus aurantium, and its natural content of p-synephrine
(e.g. up to approximately 4%), will pose any risk whatsoever to the health of Canadian
consumers.
p-Synephrine Alone
With respect to p-synephrine in single ingredient natural health products (dietary supplements)
for weight loss and body composition management, the risk of cardiovascular adverse effects in
healthy people has been overstated in the literature and probably incorrectly linked causally to
case reports. While (±)-p-synephrine tartrate has been used successfully to treat hypotension in
the dose range of 300 to 450 mg/day (equivalent to approximately 100 to 150 mg of (-)-psynephrine/day), clinical trials in healthy humans subject to acute to subchronic dosing (14 days)
at up to 50 mg/day p-synephrine have generally not shown any significant increase in blood
pressure or other cardiovascular effects. Receptor binding assays have shown that p-synephrine
has a low affinity, very low potency partial agonism at α1A-AR and partial antagonism at the α2Aand α2C- ARs (30 to 1,000 fold less active than NE) responsible for vasoconstriction, and psynephrine has extremely weak partial agonism at β1-ARs (40,000 fold less active than NE)
responsible for increased heart rate. Therefore, in contrast to ephedrine, at typical supplement
doses which are much lower than the hypotension therapeutic dose, p-synephrine is not likely to
trigger cardiovascular adverse events in healthy individuals.
p-Synephrine and Caffeine
The risk of cardiovascular adverse events is more difficult to assess due to the fact that most
clinical studies have used multi-ingredient products rather than just synephrine plus caffeine.
There is some evidence that caffeine may potentiate adverse effects from synephrine. At high
doses caffeine itself can trigger cardiovascular adverse events and may be the ingredient most
likely linked causally to some of the adverse reactions in the case reports. In the clinical studies
the dose of synephrine ranged from 6 mg to 59 mg and the dose of caffeine ranged from 150 mg
to 528 mg. While there is up to 6 weeks exposure evidence for the safety of combinations of
synephrine up to 50 mg plus caffeine up to 528 mg, and the human body may be able to
Synephrine Octopamine Caffeine HRA
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accommodate to the combined effect as has been seen for the combination of ephedrine plus
caffeine, most of the studies have been acute dosing in healthy populations and it is likely that
the risk of cardiovascular adverse events increases as levels of caffeine exceed Health Canada’s
recommended maximum daily intake for adults of 400 mg from all sources. To account for
dietary sources of caffeine, a reasonable risk mitigation approach is to limit the dose of caffeine
in natural health products to 80% of the recommended daily maximum for adults, i.e. 320
mg/day. Given the limited evidence for safety beyond six weeks and the likelihood that weight
loss products will be taken for longer than six weeks, coupled with the evidence of a potential
synergy between synephrine and caffeine, it would be consistent with the majority of the
available clinical trial evidence on p-synephrine plus caffeine combinations to apply an 80%
threshold for synephrine too. This would result in a reasonable level of confidence in the safety,
without necessarily compromising potential efficacy, of a combination of 40 mg of p-synephrine
plus 320 mg of caffeine. Such a recommendation does not preclude the submission of evidence
for higher doses or longer durations for assessment in a product licence for market authorization
in Canada.
p-Synephrine, Caffeine and Other Stimulants
In the majority of adverse reaction case reports involving products that contain Bitter Orange or
synephrine , other potential stimulants in addition to caffeine are present, including octopamine,
tyramine, N-methyltyramine, hordenine, ephedrine, yohimbine, thyroid stimulating agents such
as iodotyrosine, etc. The likelihood of a risk to the health of consumers increases significantly
with the presence of these additional ingredients which may more probably be linked causally to
the adverse event than the p-synephrine content (Stohs and Shara 2011). Such products need to
be assessed for their risk to health on a case-by-case basis, with a clear understanding of the
unique pharmacology of each ingredient rather than assumptions of similar structures providing
similar activities.
Octopamine
Due to its specificity for the β3-AR but low potency and very poor bioavailabilty, octopamine is
not likely to cause any serious adverse consequences at the doses studied clinically (e.g. 5 mg)
but its effects at doses of 100 mg or more are unknown.
Susceptible Subpopulations
In addition to the standard susceptible subpopulations of children and pregnant or breastfeeding
women, there are some other subpopulations likely to be at great risk from combinations of
synephrine, caffeine, and other stimulants.
According to Eckel et al. (2005), overweight individuals are susceptible to developing metabolic
syndrome: a multi-faceted disease, characterized by glucose intolerance (e.g., type 2 diabetes,
impaired fasting glycemia), insulin resistance, central obesity, dyslipidemia, and hypertension.
When taken together, these pathologies are associated with an increased risk of cardiovascular
disease. It is difficult to estimate the prevalence of metabolic syndrome due to the various
definitions used to characterize the syndrome; though the prevalence may be ~24% in American
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men, though varying by ethnicity and age. The syndrome has been classically seen as an adult’s
disease; but with the increasing prevalence of obesity in young people, the syndrome may be
evident even in young children. Reportedly, “each half-unit increase in [Body Mass Index] was
associated with an increase in the risk of the metabolic syndrome in overweight and obese people
(odds ratio 1•55)” (Eckel et al. 2005).
The prevalence of hypertension in an overweight population is of special concern with respect to
sympathomimetic stimulant use, as these people do not respond to pressor agents as healthy
individuals do (Fugh-Berman and Myers 2004). In the setting of metabolic syndrome including
insulin resistance, it should be noted that insulin acts as a vasodilator in healthy individuals;
therefore, the absence of a vasodilatory effect due to insulin resistance, coupled with a
vasopressor effect provided by the sympathomimetic agent(s) may result in a further elevation in
blood pressure (Eckel et al. 2005). There is evidence to suggest that individuals with essential
hypertension demonstrate increased alpha adrenergic vasoconstriction, compared to
normotensive controls. Egan et al. (1987) compared 24 overweight, hypertensive men (mean
systolic blood pressure of 145 ± 3; mean diastolic blood pressure of 100 ± 2) against 18
overweight, normotensive men (mean SBP: 122 ± 3; mean DBP: 78 ± 2). After intravenous
injection of norepinephrine, it was found that the hypertensive participants demonstrated a
statistically significant greater response in forearm vascular resistance. As synephrine is a known
vasoconstrictor with alpha adrenergic activity, the pressor responses to synephrine could be
elevated in sensitive, overweight individuals consuming weight-loss products.
Overweight individuals are at an increased risk of having these metabolic disorders and may not
have been previously diagnosed. In addition, weight-loss products would likely be taken longterm – at least for periods longer than are used in the clinical studies used to support safety of
synephrine, alone or in combination with other stimulants. For instance, the resulting chronic
sympathetic stimulation could theoretically lead to a progressive deterioration of health, as
would long-term hypertension.
Other vulnerable populations would be those consumers being treated with monoamine oxidase
inhibitors or thyroid medications, as they will be particularly susceptible to substances that may
affect pressor responses. Since synephrine has limited affinity and potency at implicated
receptors, this is more likely to occur via its effects on the NE transporter stimulating NE release.
Risk Classifications
Citrus aurantium Peel
Based on the evidence reviewed above, the botanical material Bitter Orange peel, at the doses
typically used in herbal medicine and food, is not considered to pose any risk to the health of
consumers.
p-Synephrine Alone
At doses up to 50 mg/day in healthy adults, p-synephrine is classified as Type III, meaning that
the use of, or exposure to, a single-ingredient p-synephrine product under these conditions is not
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likely to cause any adverse health consequences, except in cases where the necessary cautionary
statements (i.e. contraindicated in children, pregnancy, and breast-feeding, do not use if you are
taking blood pressure medications (either hypertensives or antihypertensives), thyroid
medications, sympathomimetics, or monoamine oxidase inhibitors (MAOIs)) are lacking, which
would result in a risk classification of Type II.. The definitions of Type II and III are set out in
the Health Products and Food Branch Inspectorate - Recall Policy (POL-0016) (Health Canada
2006).
At doses above 50 mg/day, p-synephrine approaches the dose used as a prescription drug in
Europe for the treatment of hypotension. While it is possible to be exposed to a dietary source of
as much as 70 mg of p-synephrine from a cup of Cleopatra mandarin orange juice, this is not a
common item in the diet and the dose-response curve for p-synephrine between 50 mg and
therapeutic doses of the racemic tartrate are not adequately characterized to be categorical as to
safety. Therefore, in the absence of a product-specific review of safety under specific
recommended conditions of use, as would be accomplished through assessment of a product
licence for market authorization, the application of precaution is a legitimate decision making
approach within risk management. Such unauthorized products are therefore classified as a Type
II risk to health, meaning that the use of, or exposure to, such a product may cause temporary
adverse health consequences or where the probability of serious adverse health consequences is
remote (Health Canada 2006). A “serious adverse reaction” means a noxious and unintended
response to a natural health product that occurs at any dose and that requires in-patient
hospitalization or prolongation of existing hospitalization, that causes congenital malformation,
that results in persistent or significant disability or incapacity, that is life threatening or that
results in death (Government of Canada 2011).
p-Synephrine and Caffeine
Products providing 40 mg/day or less of p-synephrine plus 320 mg/day or less of caffeine, are
classified as Type III, except in cases where the necessary cautionary statements (i.e.
contraindicated in children, pregnancy, and breast-feeding, do not use if you are taking blood
pressure medications (either hypertensives or antihypertensives), thyroid medications,
sympathomimetics, or monoamine oxidase inhibitors (MAOIs)) are lacking, which would result
in a risk classification of Type II (Health Canada 2006).
Products exceeding either threshold dose or products lacking the cautionary statements (i.e.
contraindicated in children, pregnancy, and breast-feeding, do not use if you are taking blood
pressure medications (either hypertensives or antihypertensives), thyroid medications,
sympathomimetics, or monoamine oxidase inhibitors (MAOIs)), are classified as a Type II risk
to health.
p-Synephrine, Caffeine and Other Stimulants
Such products have been implicated in many serious adverse reaction case reports. Causality is
not likely due to the p-synephrine content on its own, rather to other ingredients such as
octopamine in high doses or thyroid drugs such as iodotyrosine. The risk to human health must
be assessed on a case by case basis. Given the nature of the observed adverse reactions, it is
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probable that some of these products will be assessed as posing a Type I risk to health, meaning
that there is a reasonable probability that the use of or exposure to such a product will cause
serious adverse health consequences or death (Health Canada 2006).
p-Octopamine
Based on its known pharmacology, p-octopamine at doses up to 50 mg/day in healthy adults is
classified as Type III. At doses above 50 mg/day, due to the paucity of human clinical data, in
the absence of a product-specific review of safety under specific recommended conditions of use,
as would be accomplished through assessment of a product licence for market authorization, the
application of precaution is a legitimate decision making approach within risk management.
Such unauthorized products are therefore classified as a Type II risk to health.
Exacerbating Conditions
Due to the extremely limited evidence for the safety of chronic use of p-synephrine alone or in
combination with caffeine or other ingredients in vulnerable subpopulations, the following
cautionary statements (or words to these effects) should be on product labels to mitigate the risk
of potentially serious adverse reactions:
 Contraindicated in children, pregnancy, and breast-feeding.
 Do not use if you are taking blood pressure medications (either hypertensives or
antihypertensives), thyroid medications, sympathomimetics, or monoamine oxidase
inhibitors (MAOIs).
Recommendations for Managing the Risk
Consistency of Approach with Previous NHP HRAs
The recommended Health Risk Classification criteria above are consistent with the Health Risk
Assessments (Health Hazard Evaluations) previously prepared by Health Canada with respect to
the products Thermonex (Type I, 2004-04-13), Slim System 8 (Type II, 2004-12-20), No. 1
Protocole Minceur (Type III, 2005-06-10), MetaSlim (Type III 2006-02-22), Synerate (Type I,
2010-12-31), and Lipo-6X (Type I, 2011-01-25).
Consistency of Approach with Similar Drugs
Sympathomimetic agents have a poor history of long-term success in the treatment of obesity.
From earlier experiences with amphetamine and its analogs, to more recent drugs with direct
effects on adrenergic receptors or indirect effects from release of catecholamines or inhibition of
reuptake, cardiovascular toxicity (strokes and cardiac arrhythmias) has been the major concern
(Inchiosa 2011). For example, the European Medicines Agency on January 1, 2010, advised
against continuing to prescribe sibutramine based on serious cardiovascular adverse reactions
(Inchiosa 2011). Health Canada (2010a,b) and the FDA (2010c) also saw the voluntary
withdrawal of all marketed sibutramine drugs for that reason. Thus, it was appropriate to
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thoroughly assess the potential risks to health of p-synephrine alone and in combination with
caffeine and other stimulants, particularly considered the large number of reported adverse
reactions but poor quality of those reports.
Limits for Syneprhine in Other Jurisdictions
The Therapeutic Goods Administration (TGA) has established a 30 mg total daily dose for
synephrine (synonym oxedrine) content in OTCs (NDPSC 2003). The 30 mg limit, which was
also adopted by New Zealand (Medsafe 2003), was based on the therapeutic dose for oxedrine
tartrate for hypotension as described in Martindale of 100-150 mg three times daily (Sweetman
2007). The National Drugs and Poisons Schedule Committee found little evidence of harmful
effects at dosage levels of 30 mg per day or less, in divided doses, and considered a 10-fold
safety factor to be an adequate safety margin. Members highlighted that there was sufficient
evidence to suggest the significant potential for oxedrine to cause cardiotoxicity at low dose
levels. Furthermore, the Committee also noted that a 28-year old Australian man suffered a large
myocardial infarction while abusing oxedrine tablets, although no data on the dosage level was
provided in the case report. In consequence to the cut-off limit of 30 mg/day, an entry in
Schedule 4 of the Standard for the Uniform Scheduling of Drugs and Poisons (now the Standard
for the Uniform Scheduling of Medicines and Poisons) has been included: “Oxedrine
[synephrine] for human internal use except in preparations labelled with a recommended daily
dose of 30 mg or less of oxedrine.” Schedule 4 includes ingredients intended for use by
prescription only (Poisons Standard 2010).
The Food Safety Commission of Malta also permits a 30 mg maximum per day in foodstuffs
(corresponding to 800 mg C. aurantium with 4% synephrine); foodstuffs exceeding this dose
must be sold from a pharmacy. The content of synephrine must be stated on the label along with
a warning against use by patients with cardiovascular disease and/or hypertension, and
recommendations not to be used during pregnancy or lactation or by children under 12 years
(Government of Malta 2007).
The Italian Ministry of Health also uses a limit of 30 mg synephrine and requires that the label
state the synephrine content at the advised dosage as well as warnings against use in the presence
of cardiovasculopathies and/or arterial hypertension (Mattoli et al. 2005).
Conclusion/Risk Management Strategy
There are a number of limitations that are common to all the available clinical studies, including:
 The sample sizes of the studies are extremely small. Although the possible cardiovascular
effects to products in this class are potentially very serious, they are also fairly rare. The
available studies are not sufficiently broad in scope to support the safety in a general
consumer population, especially when the population targeted for these products consists of
largely overweight/obese individuals, who are subject to various co-morbidities. This
limitation is inherent to all available randomized, controlled trials. In effect, appropriate
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


evidence for safety, especially for rare adverse events, should come by way of sufficient
epidemiological studies;
In addition to the limited sample sizes, the study populations are also generally healthy, even
if some studies include overweight individuals. This adds further to the incomparability of
available studies and extrapolation to the general population;
None of the studies include a justification for their sample sizes, nor an indication of power.
This is a critical oversight, as it calls into question all of the findings. Lack of an effect could
very well be a genuine lack of an effect, or simply an inability to detect an effect;
The studies are all of very short duration – another inherent deficiency seen when using
randomized, controlled trials to support safety. As the nature of the cardiovascular events
could depend on long-term exposure (e.g., chronic sympathetic over-stimulation), the shortterm studies are not adequate to support long-term safety. The authors of Seifert et al. (2011)
comment that, “longer term studies are required to assess [the effects on heart rate and blood
pressure] under conditions similar to those encountered when using the product in
conjunction with a long term weight loss program.”
In summary, this Health Risk Assessment does not address the issue of efficacy, which must be
assessed through the product licensing process for each individual product.
However, based on new clinical studies and published reviews of safety information, it has been
possible to revise the synephrine and caffeine recommendations prepared previously by Health
Canada (2010c) in order to reduce unnecessary compliance actions on products that do not
present as serious a risk to health as had been judged previously. This will allow resources to be
focused better on compliance and enforcement of more risky products.
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