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Bitter orange dietary supplements

Category: Food

Type

Involuntary

Introduction and description

Bitter orange, Seville orange, sour orange, bigarade orange, or marmalade orange refers to a citrus tree (Citrus × aurantium) and its fruit. 

But the Bitter orange described here is the chemical extract that is employed in ‘herbal medicine’ as a stimulant and appetite suppressant [used for example in the treatment of obesity], or sports performance ‘enhancer’; due to its active ingredient, synephrine. Following bans on the stimulant ephedra, bitter orange has also been substituted into "ephedra-free" herbal weight-loss products by dietary supplement manufacturers.

Bitter orange supplements have been linked to a number of serious side effects, one of which is hallucinations, and another is death.

Classification as food

One of the principal problems with this supplement is that it is classified as a ‘food’ when it is clearly a drug.  The extract of bitter orange (and bitter orange peel) is marketed as a ‘dietary supplement’ and like most dietary supplement ingredients, bitter orange does not undergo formal safety testing.

Case reports have linked bitter orange supplements to strokes, angina, and ischemic colitis.  Furthermore, Bitter orange has also been shown to have serious drug interactions with drugs such as statins.  Taking bitter orange with medications used for depression has also resulted in serious side effects, including fast heartbeat, high blood pressure, seizures, nervousness, and others.

The lack of controls has caused death.  A ‘healthy young man’ suffered a myocardial infarction (heart attack) linked to bitter orange.  The investigation into his death found that dietary supplement manufacturers had replaced ephedra with bitter orange.

The Fruit and its chemicals

Citrus × aurantium is a hybrid between Citrus maxima (pomelo) and Citrus reticulata (mandarin) and is a plant belonging to the family Rutaceae.   Many varieties of bitter orange are used for their essential oil, and are found in perfume, used as a flavouring or as a solvent. The Seville orange variety is used, for example, in the production of marmalade.

Citrus aurantium (bitter orange) is used to obtain ‘ fruit extracts’.  These are very concentrated chemicals that have been extracted from the entire fruit.  The most important biologically active constituents of the C. aurantium fruits are phenethylamine alkaloids

  • Octopamine
  • Synephrine
  • tyramine
  • N-methyltyramine and
  • Hordenine

In tests done on samples, examining for p-synephrine and the 5 other biogenic amines: octopamine, phenylephrine (m-synephrine), tyramine, N-methyltyramine, and hordenine, p-Synephrine was found to be the primary biogenic amine present in all materials tested, accounting for >80% of the total biogenic amine content in all samples.

Other research has confirmed this finding, showing that of the adrenergic amines of natural origin, synephrine has been found to be the main constituent of C. aurantium fruits and extracts; the other alkaloids are either absent or present in only low concentrations.

Symptoms in more detail

Synephrine is present in both the peel and the edible part of Citrus fruit.  It is known that synephrine and the other amines found in C. aurantium have adverse effects on the cardiovascular system, owing to adrenergic stimulation. It has pharmacological activities such as

  • Vasoconstriction
  •  elevation of blood pressure and
  • relaxation of bronchial muscle
Synephrine exists in three different positional isomers; however, only p- and m-synephrine have been described in weight-loss products. …. The growing use of synephrine has raised concerns since it has been accompanied by reports of adverse effects. Cardiac adverse events, including hypertension, tachyarrhythmia, variant angina, cardiac arrest, QT prolongation, ventricular fibrillation, myocardial infarction, and sudden death, have been the most common adverse effects associated with synephrine intake. PMID:  21075161

and

In this review of the many Dietary supplements promoted for the management of hypertension, 4 products with evidence of possible benefits

 - coenzyme Q10
 - fish oil
 - garlic
 - vitamin C

and 4 that were consistently associated with increasing blood pressure were found

 - ephedra
 - Siberian ginseng
 - bitter orange
 - licorice.

The goals and objectives of this review are to discuss the regulation of DS, evaluate the efficacy of particular DS in the treatment of hypertension, and highlight DS that may potentially increase blood pressure.  PMID:  22747620

The eHealthme website collects ADRs in the USA submitted by doctors to the FDA and SEDA and summarises them over time.  Of the ADRs it analysed, and after less than a month of use of these supplements, symptoms reported included

  • Anxiety
  • Blood glucose increased
  • Corneal oedema (corneal swelling)
  • Depression
  • Emotional distress
  • Endophthalmitis (inflammation of the internal coats of the eye)
  • Pain
  • Pigment dispersion syndrome (affliction of the eye that can lead to a form of glaucoma)
  • Pulmonary oedema (fluid accumulation in the lungs)
  • Renal failure (kidney dysfunction)

These are the classic side-effects of stimulants.  Longer term, people have complained of drug dependence.  Overall a whole host of other problems have emerged over time

  • Abdominal distension and pain
  • Anaphylactic reaction (serious allergic reaction)
  • Cardiac failure
  • Cardio-respiratory arrest (sudden dysfunction of heart and lungs)
  • Hyponatraemia (abnormally low level of sodium in the blood; associated with dehydration)
  • Miosis (constriction of the pupil of the eye, resulting from a normal response to an increase in light)
  • Multi-organ failure (multisystem organ failure)
  • Acute Renal failure (rapid kidney dysfunction)

 

Commercial orange juice

Although this entry has concentrated on supplements, Synephrine, is the main protoalkaloid in Citrus species.  It is found in the peel but the edible parts of mandarins also contain the chemical.  In one study, the synephrine concentration of the juices of Citrus unshiu mandarins harvested from 10 different groves located in a major growing region in California was analysed for the physicochemical properties of the juices.   The synephrine values among 10 groves ranged from 73.3 to 158.1 mg L (-1). The more acid and the less ripe, the more synephrine. I could find no paper to support the following hypothesis, but hyperactivity, ADHD and a host of other childhood problems related to adrenaline, may be being caused by commercially produced high concentrate orange juice from the ‘wrong oranges’. In the study mentioned, the overall mean synephrine concentration of 92.8 mg L (-1) is up to 6-fold higher than values previously determined for orange juices.

References and further reading

  • J AOAC Int. 2007 Jan-Feb;90(1):68-81. - Determination of synephrine in bitter orange raw materials, extracts, and dietary supplements by liquid chromatography with ultraviolet detection: single-laboratory validation. - Roman MC1, Betz JM, Hildreth J.  PMID:  17373438
  • J Chromatogr A. 2007 Aug 17;1161(1-2):71-88. Epub 2007 Jun 7. - Chromatographic and electrophoretic methods for the analysis of phenethylamine alkaloids in Citrus aurantium. - Pellati F1, Benvenuti S.  PMID: 17582424
  • J Clin Hypertens (Greenwich). 2012 Jul;14(7):467-71. doi: 10.1111/j.1751-7176.2012.00642.x. Epub 2012 May 14.  Dietary supplements and hypertension: potential benefits and precautions. - Rasmussen CB1, Glisson JK, Minor DS.
  • Bouchard NC, Howland MA, Greller HA, et al. Ischemic stroke associated with use of an ephedra-free dietary supplement containing synephrine. Mayo Clinic Proceedings. 2005;80(4):541-545.
  • Firenzuoli F, Gori L, Galapai C. Adverse reaction to an adrenergic herbal extract (Citrus aurantium). Phytomedicine. 2005;12(3):247-248.
  • Gange CA, Madias C, Felix-Getzik EM, et al. Variant angina associated with bitter orange in a dietary supplement. Mayo Clinic Proceedings. 2006;81(4):545-548.
  • Nykamp DL, Fackih MN, Compton AL. Possible association of acute lateral-wall myocardial infarction and bitter orange supplement. Annals of Pharmacotherapy. 2004;38(5):812-816. 
  • Shara M, Stohs SJ, Smadi MM. Safety evaluation of p-synephrine following 15 days of oral administration to healthy subjects: a clinical study. Phytotherapy Research. 2018;32(1);125-131.
  • Smith TB, Staub BA, Natarajan GM, et al. Acute myocardial infarction associated with dietary supplements containing 1,3 dimethylamine and Citrus aurantium. Texas Heart Institute Journal. 2014;41(1):70-72.
  • Stohs SJ, Badmaev V. A review of natural stimulant and non-stimulant thermogenic agents. Phytotherapy Research. 2016;30(5):732-740.
  • Thomas JE, Munir JA, McIntyre PZ, et al. STEMI in a 24-year-old man after use of a synephrine-containing dietary supplement: a case report and review of the literature. Texas Heart Institute Journal. 2009;36(6):586-590.
  • Psychosomatics. 2011 Nov-Dec;52(6):579-82. doi: 10.1016/j.psym.2011.06.003.  "Ephedra-free" diet pill-induced psychosis. Retamero C1, Rivera T, Murphy K. Department of Psychiatry and Behavioral Sciences, Temple University School of Medicine, Philadelphia, PMID: 22054631
  • Food Chem Toxicol. 2011 Jan;49(1):8-16. doi: 10.1016/j.fct.2010.11.007. Epub 2010 Nov 12. - Synephrine: from trace concentrations to massive consumption in weight-loss.  Rossato LG1, Costa VM, Limberger RP, Bastos Mde L, Remião F.REQUIMTE-Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.

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