Bitter Orange

Bitter Orange: What is it and how does it work in the body?

• Bitter orange is known by a few different names. The scientific name for the small citrus tree is Citrus aurantium. It is also known by Zhi Shi, Seville orange, and sour orange.

• These names refer to the small citrus tree, the peel, and the fruit.

• The active ingredients are synephrine and octopamine which are structurally similar to epinephrine and norepinephrine.

• These structures are believed to affect alpha and beta-3 receptors, but affect beta-1 and beta-2 receptors less actively, theorized to have fewer CNS side effects.

• However, there are conflicting studies on the mechanism of action of synephrine specifically.

• Some studies report the beta-3 activity stimulate the heart and act in systemic vasodilation, but primarily stimulate alpha-1 adrenergic receptors due to structural similarity to phenylephrine which would result in vasoconstriction and increase of blood pressure.

What is it used for and at what dosage?

• Weight loss supplement by increasing energy—expenditure. There has been evidence of effective weight loss at a synephrine dose of 32 mg daily, and doses up to 80 mg/day have been used for the treatment of obesity.

Evidence for or against its different uses:

• All the current studies investigate bitter orange in combination with other supplements, such as caffeine, guarana, white willow bark, ginger root extract, and ma huang.

• There were no studies found of investigating bitter orange as a supplement alone.

• In a study investigating which isomers were present in a weight loss supplement containing bitter orange, the label reported it only contained one isomer (m-synephrine), but the authors’ analysis proved that it contained two types (m-synephrine and p-synephrine).

• p-Synephrine is known to cause more CNS stimulation.

• One of the first clinical studies was a 6-week, double-blind, placebo-­ controlled randomized study involving 23 subjects.

• This study investigated bitter orange on weight loss examined a mixture of bitter orange, St. John’s wort, and caffeine compared to a control group, placebo group, and an active group. The

  results did show that after 6 weeks, there was a statistically significant loss in body fat and percent fat in the active group compared to control/placebo, however, no significant differences between groups for body weight, basal metabolic rate, blood pressure, heart rate, or EKG (loss of −2.9% compared to 0.8%).

• These results per the authors suggest that bitter orange in combination with St. John’s wort and caffeine was safe and effective for weight loss in combination with diet and exercise. However, this study should be interpreted with caution due to the confounding factors of other supplements involved, as well as the statistical analysis being performed within the group, it was not performed between groups.

• Another trial examined the cardiovascular effects involving 15 subjects of a single dose of bitter orange (6% synephrine). Heart rate and systolic and diastolic heart rate were measured at baseline and every hour for 6 h after administration.

• Increase or changes in systolic and diastolic blood pressure and heart rate were observed for 5 h following administration of bitter orange.

• However, another randomized, open-label, placebo-controlled crossover design study examined blood pressure and heart rate with synephrine or water placebo, measuring blood pressure hourly for 5 h, and there was no effect of blood pressure or pulse.

• Finally, a double-blind, placebo-controlled safety study was conducted in 67 moderately overweight adults (mean BMI of 30.8) and were assigned one of three treatments, p-synephrine, a combination of p-synephrine with naringin and hesperidin, or placebo for 60 days twice a day.

• There were no differences among the three groups for lipid profiles, liver enzymes, electrolytes, or CBC, and no differences in systolic or diastolic blood pressures were observed.

• However, the placebo group experienced a significant reduction in heart rate from baseline compared to the other active treatment groups. There was no data noted on body weight changes.

Safety concerns, side effects, and precautions:

• Patients with premorbid conditions such as cardiac arrhythmias, hyperthyroidism, and narrow angle glaucoma due to the vasoconstriction effect of synephrine.

• There has been documentation of a 38-year-old man who suffered an ischemic stroke after taking a dietary supplement containing bitter orange for 1 week. No other etiology could be identified as the individual did not suffer from an atherosclerotic history or have any other comorbidities.

• Another case involves a 52-year-old woman with hypothyroidism (on thyroxine) who had been consuming bitter orange daily (containing 30 mg/daily) who had developed unremitting tachycardia.

• A 22-year-old male developed rhabdomyolysis after consuming a bitter orange weight loss formula. He developed fatigue, dehydration, and myalgias while exercising.

• There has not been enough evidence regarding safety and efficacy to safely administer to any patient who is pregnant or lactating.

Interactions with medications:

• Bitter orange interacts intestinal CYP3A4 and therefore should be avoided in drugs such as amiodarone, anxiolytics, antidepressants, antiviral medications, calcium channel blockers, dextromethorphan, prokinetic agents to aide in digestion, vasoconstricting medications, and other weight loss formula pharmaceuticals

Key Web Sources

• 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;229:698–704.

• Bent S, Padula A, Neuhaus J. Safety and efficacy of citrus aurantium for weight loss. Am J

  Cardiol. 2004;94:1359–61.

• Penzak SR, Jann MW, Cold JA, Hon YY, Desai HD, Gurley BJ. Seville (sour) orange juice:

  synephrine content and cardiovascular effects in normotensive adults. J Clin Pharmacol.

  2001;41:1059–63.