Home' Australian Pharmacist : August 2011 Contents Vol. 30 -- August #08
differences in action between racemic
(d,l-) and pure d- or l- compounds?
Blumenthal noted that injected
synephrine and bitter orange showed a
hypertensive effect in these studies, but
it was not so with oral use. He warned
that while the review part of Fugh-
Berman and Myers article was a valued
contribution to the literature because
of a general lack of 'authoritative
published reviews', that 'warnings about
bitter orange safety are speculative
and not based on solid scientific or
Further, in a letter to the Editor of USA
Today concerning an article, Lax rules
let supplements lurk as health threats
(27 Oct 2004;13A), Blumenthal noted
in addition to the point about injection
of the test substances that 'bitter
orange is considered a GRAS (generally
regarded as safe) food ingredient by
the FDA for use in candies, soft drinks
and other foods and it is the primary
ingredient in many brands of orange
marmalade', adding 'to date we have
found no plausible evidence suggesting
it is unsafe when consumed orally in
The constituents responsible for the
claimed adverse effects are generally
not listed in traditional pharmacognosy
or herb books, which only tend to
mention hesperidin, neohesperidin or the
volatile oil. Bitter orange is also claimed
to contain N-methyltyramine (NMT),
octopamine and synephrine, all related
to adrenaline (epinephrine) and therefore
potentially able as alpha1-adrenergic
receptor agonists to constrict blood
vessels, and increase blood pressure
and heart rate.2 Perhaps surprisingly,
Duke's authoritative text on GRAS herbs
and their phytochemical constituents15
does not mention the presence of NMT,
octopamine and synephrine in a number
of varieties of bitter orange, but lists
them in lemon (C. limon L.), mandarin (C.
reticulata B.), sweet orange (C. sinensis
L.), and grapefruit (C. X paradisi). This
likely reflects the date and extent of
original laboratory research rather than
the facts of actual occurrence.
active at alpha and beta-adrenergic
receptors and an interesting,
detailed commentary is available in
a bodybuilding and fitness forum.16
Bodybuilders are obviously interested
in NMT as a useful dietary supplement
and the writer 'Synapsin' has presented
a detailed analysis of its pharmacology.
Stimulation of adrenergic, dopaminergic
and serotonergic neurotransmitter
levels, insulin secretion and pancreatic
secretion, and decrease of blood
sugar levels were all of interest, its
actions being interpreted as peripheral
NMT is converted to synephrine
phenol )] by dopamine beta-hydroxylase
in the body. Synephrine has taken on
the mantle of a popular drug alternative
to ephedrine, while not being
convertible to illegal methamphetamine
due to the presence of the 4-phenolic
group.17 Synephrine is a popular
constituent of slimming agents
and, as mentioned previously, has
been suggested to be linked to
adverse effects such as ischemic
stroke, hypertension and myocardial
infarction.17 Whether these effects
are real is a matter of some credible
debate.11,12 It occurs naturally in many
plants and especially bitter orange, the
Asian variety Zhi shi being quite a rich
source (about 0.2%), and in Satsuma
Finally there is octopamine [4-(2-amino-
1-hydroxy-ethyl)phenol], an invertebrate
neurotransmitter/hormone which, as the
name suggests, was first isolated from
octopii, but also occurs in citrus fruits.15
In insects, crustaceans and spiders it is
used in energy-demanding behaviours
such as egg-laying, flying, jumping,
learning and memory (in honey bees and
fruit fly). There is an amusing anecdote
regarding the emerald cockroach wasp
which 'stings the cockroach in the head
ganglion, blocking the octopamine
receptor, thus inhibiting normal escape
responses and causing excessive
grooming responses'. The cockroach
'becomes docile and the wasp leads it
to the wasp's den by pulling its antenna
like a leash!'19 In mammals, octopamine
is thought to mobilise adipose fat stores
and hence has often been added to
slimming aid preparations.15
The aforementioned 'party alternatives'
include preparations such as Buzzz.7
Buzzz contains 'chocolate, honey, bitter
orange, octopamine, L-tyrosine, saffron,
kanna (Sceletium tortuosum), and E102
(tartrazine)'20 and, as stated previously,
is quite an eclectic mix. The Australian
franchised Happy High Herbs selling
these mixtures as well as a range of
medicinal herbs and other preparations
have not been without their occasional
brush with regulatory authorities such
as the TGA in the 1990s, concerned
with health and safety issues, but
I understand no further action has
It will be interesting to see how the
story of party alternative herbal highs
unfolds. In the meantime I will get my
morning highs from a liberal spread
of marmalade on my toast. However,
I'm certain the presence of sugar and
bread does not guarantee any beneficial
slimming effects! Now as I chew, I will
quietly muse on the unknown content of
NMT, synephrine and octopamine in my
marmalade and their potential effects on
my day's activities.
1. Evans WC. Trease and Evans' Pharmacognosy.14th edn.
London: WB Saunders; 1996. p 270.
2. Wikipedia. Bitter orange [online]. At: http://en.wikipedia.
org/wiki/Bitter_orange and references contained therein.
3. Masefield GB, et al. The Illustrated Book of Food Plants.
Oxford University Press; 1969. This edition by Peerage
Books; 1985. p 64.
4. British Pharmacopoeia Commission Secretariat of the
Medicines and Healthcare Products Regulatory Agency.
The British Pharmacopeia 2011. London, UK; 2011.
5. Reference 1. p 251.
6. Grieve M. A Modern Herbal (1931). Chatham UK: Tiger
Books International (Cresset Press);1992. p 601--602.
7. Happy High Herbs [online]. At: www.happyhighherbs.
8. Bown D. The Royal Horticultural Society Encyclopedia of
Herbs and their Uses. London: BCA (Dorling Kindersley);
1995. p 262--3.
9. White LB, Foster S. The Herbal Drugstore. Rodale; 2000.
10. Stohs SJ, Preuss HG, Keith SC, et al. Effects of
p-synephrine alone and in combination with selected
bioflavonoids on resting metabolism , blood pressure,
heart rate and self reported mood changes. Int J Med
Sci. 2011; 8(4):295--301.
11. American Botanical Council. Safety of bitter orange
documented in scientific review [online] 2011. At http://
12. Washington Post runs story on potential risks of bitter
orange [online]. At: http://cms.herbalgram.org/press/
13. Fugh-Berman A, Myers A. Citrus aurantium, an ingredient
of dietary supplements marketed for weight loss: current
status of clinical and basic research. Exp Biol Med. 2004;
14. ABC submits letter to Editor of USA Today responding to
bitter orange article [online]. At: http://cms.herbalgram.
15. Duke JA. Handbook of Phytochemical Constituents of
GRAS Herbs and other Economic Plants. Boca Raton: CRC
Press; 1992. p 171--86.
16. Synapsin. N-Methyltyramine (4-hydroxyN-
methylphenethylamine) -- a detailed overview of
N-methyl tyramine [online]. At: http://forum.bodybuilding.
17. Wikipedia. Synephrine [online]. At: http://en.wikipedia.
18. Wikipedia. Octopamine [online]. At: http://en.wikipedia.
19. Nature News. How to make a zombie cockroach [online].
Sept 2007; 29. At: www.nature.com/news/2007/071129/
20. Bastians K. Personal communication. 7 Jun 2011.
21. Doherty M. Authorities unhappy with herbal highs.
Tweed Shire Echo; 11 Sept 2008.
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