aurantium extract product Advantra Z ® while the other half of the subjects received the placebo Table 2. Heart rate and blood pressures were determined at the start of the study and after six weeks. No significant differences were observed between the treated and placebo control groups at the conclusion of the study with respect to these cardiovascular parameters.

No effects on body weight were reported. This study represents the highest dose of p -synephrine for the longest period of time that has been reported. The study was presented at a scientific meeting but never published.

The product Ripped Fuel Extreme Cut TM contained 21 mg p -synephrine and mg caffeine, as well as other ingredients including herbal extracts of green tea, ginger root, cocoa seed, willow bark, and wasabi.

The product or placebo was taken one hour prior to 30 min of moderately intense exercise. No significant treatment-related differences in systolic blood pressure, heart rate or body temperature were observed.

Product-related increases in diastolic blood pressure 8. Exercise was perceived as being less strenuous after consumption of the product. Due to the poly-alkaloidal and protoalkaloidal nature of this product, the factor or factors responsible for the effects on blood glucose and diastolic blood pressure cannot be determined.

Seifert et al. The product contained 13 mg p -synephrine as Advantra Z ® , mg caffeine as guarana , and The study involved 14 females and 9 males in a placebo-controlled, crossover design.

Subjects ingested one capsule with each of three meals on day one of treatment, and one more capsule on the morning of the second day. Data were collected 60 min after the last administration of the product.

No differences were observed in heart rate or blood pressure following treatment. This was an acute study which did not provide information on long-term effects, but did demonstrate an increase in energy expenditure.

Stohs et al. The study was a randomized, placebo-controlled, double blind design with the vehicle for the p -synephrine being one ounce of tomato juice. The amount of p -synephrine in the product was verified by independent analysis. Measurements were taken at baseline prior to consuming the product and at 75 min.

At this time point, a 6. No significant effects were observed with respect to blood pressure or heart rate, nor were there any significant differences in responses to a 10 item self-report questionnaire which addressed such issues as nervousness, tension, anxiety, hunger, energy, headache, general discomfort, and sleepiness.

Longer term safety and efficacy studies involving p -synephrine alone are warranted. The amount of p- synephrine in the capsules was determined by high pressure liquid chromatographic analysis. Electrocardiograms, blood pressures, heart rates, blood chemistries and blood cell counts with differentials were determined at baseline, 30 min, 60 min, 90 min, 2 hours, 4 hours, 6 hours and 8 hours, as well as after 5, 10 and 15 days.

Blood samples were drawn after 2 hours after the first dose as well as at 5, 10 and 15 days to measure p -synephrine levels to ensure compliance. p -Synephrine had no significant effect on heart rate, blood pressure, blood chemistries, or blood cell counts, and caused no cardiovascular abnormalities.

Bloomer et al. Methyl-synephrine is purported to occur in nature, does not occur in bitter orange extract, and is of synthetic origin in this product and other products that have been marketed. For the sake of completeness, the results of these studies will be summarized, but these results will not be incorporated into the general discussion of bitter orange extract and p -synephrine provided below.

Both studies examined the effects of the product on metabolic rate, and plasma free fatty acids, glycerol, norepinephrine and epinephrine levels. The initial study [ 38 ] measured changes over a 90 min time frame in 10 healthy male subjects. The second study [ 39 ] measured the same parameters over a six hour time frame in 10 healthy male and 10 healthy female subjects.

Increases in each of the parameters were observed, with a It is also important to note that significant increases in heart rate as well as systolic and diastolic blood pressure occurred in both studies in response to the consumption of the product. The authors note that the product may be useful in healthy, normotensive, closely monitored individuals.

However, it is not a product that should be recommended to the general public. In a study similar to those reported by Bloomer et al. Over a three hour time period following ingestion of the product significant increases in resting oxygen uptake and caloric expenditure were occurred.

However, increases in heart rate, systolic blood pressure, tension and confusion were also observed, confirming the highly undesirable properties of this synthetic product.

Stohs [ 41 ] has reviewed and assessed the 22 FDA adverse event reports AERs from April through October associated with bitter orange C. aurantium -containing products, as well as 10 clinical case reports published during this time interval regarding the possible involvement of bitter orange-containing weight management products with cardiovascular incidents and other adverse events.

In all reported AERs and case cases, the products involved were poly-herbal, poly-alkaloidal and poly-protoalkaloidal. Adverse events that have been purported in conjunction with the published clinical case reports included: acute lateral-wall myocardial infarction, exercise-induced syncope associated with QT prolongation, ischemic stroke, ischemic colitis, vasospasm and stroke, variant angina, coronary vasospasm and thrombosis, exercise induced rhabdomyolysis, ST segment myocardial infarction, and ventricular fibrillation [ 41 ].

In one case report it was suggested that a bitter orange-containing dietary supplement may have masked bradycardia and hypotension while exacerbating weight loss in an individual with anorexia nervosa, although no evidence was provided that an adverse event had actually occurred.

Although the products consumed were all multi-ingredient, in each case reference was specifically made to C. aurantium, bitter orange or p -synephrine as the most likely causative agent.

A more probable culprit for at least some of these effects may have been the high caffeine intake associated with the products in question. Another factor to be considered is the occurrence of up to mg p -synephrine per quarter liter of various Citrus juices [ 42 , 43 ] which are widely consumed without the report of adverse events.

Millions of individuals ingest p -synephrine and bitter orange-containing food products as orange juices and marmalades as well as dietary supplements on a daily basis. Therefore, although these case reports should raise the level of awareness with regard to the use of complex weight management products, it is not possible to extrapolate the cause of these adverse effects to the p -synephrine which may have been present in the products.

No evidence showing a direct link between bitter orange extract and the adverse events is provided [ 41 ]. A total of 23 published and unpublished studies involving a total of approximately total human subjects were reviewed.

The authors located information regarding the unpublished studies through presentations at scientific meetings and availability of research reports on the internet, as well as information from the investigators involved in the studies.

Seven of the studies were not published in peer reviewed journals [ 17 - 20 , 25 , 33 , 37 ] Table 2. However, six of these studies were presented at national meetings [ 18 - 20 , 25 , 33 , 37 ], and one of these six studies is in the process of being submitted for consideration for publication [ 37 ].

As noted in the references, information including presentations and final reports are available on the internet regarding these unpublished studies.

The results associated with these unpublished studies Table 2 in general are consistent with the results of the published studies Table 1.

Five published studies [ 6 , 24 , 27 , 31 , 36 ] and two unpublished studies [ 33 , 37 ] reported no cardiovascular effects when using p -synephrine bitter orange only containing products.

The published studies involved a total of subjects with a total of 31 subjects in the two unpublished studies. However, in one of these studies [ 24 ] consisting of 12 subjects it is not clear that effects on heart rate and blood pressure were specifically examined, with the authors simply reporting that no adverse effects were observed.

Five published studies [ 15 , 21 , 22 , 26 , 30 , 35 ] using p -synephrine in combination with other ingredients reported no cardiovascular effects. A total of 88 subjects were involved in these studies. Small cardiovascular effects were reported by Bui et al.

Small cardiovascular effects were reported for three studies that involved subjects consuming p -synephrine plus caffeine [ 28 , 32 , 34 ].

reported an increase in heart rate [ 28 ] and diastolic blood pressure [ 34 ] 10 subjects. Upon careful review, the study of Haller et al. p -Synephrine Advantra Z ® alone had no effect on systolic or diastolic blood pressure.

The authors reported an increase in heart rate six hours after treatment. The half-life of p -synephrine is two to three hours [ 28 , 34 , 45 ]. As a consequence, an increase in heart rate after two to three half-lives when the p- synephrine blood levels will have dropped to one-fourth to one-eighth the peak blood levels would not be expected.

Furthermore, a major complicating factor is that all subjects consumed a meal three hours after ingesting the p -synephrine The cardiovascular and thermic effects of food are well known [ 31 ], and an increase in heart rate in the control group was also observed.

Thus, it is not plausible to attribute the increase in heart rate to p -synephrine, or an increase in heart rate and blood pressure to a product that contained very little p -synephrine 5. This study did show that the commercial product Xenadrine EFX® which contained only 5.

This product was reported to also contain 5. aurantium extracts are either devoid of octopamine or contain only trace amounts [ 3 ], thus the product being used [ 28 ] appears to have been adulterated.

Hansen et al. These doses represent over 13 times the usual daily dose for p -synephrine and the equivalent of the caffeine in about three cups of coffee given together as a single bolus dose to these animals. When caffeine was added, increases in heart rate and blood pressure were observed [ 46 ].

These studies indicate that in rats at very high doses of p -synephrine the combination with caffeine may result in cardiovascular effects. However, due to the highly inequivalent dosing between this study in rats and typical dosing in humans, the results of this study in rats cannot be directly extrapolated to humans.

A dose of 3. Various studies indicate that the lipolytic activity of p -synephrine is due to binding to β-3 adrenergic receptors in adipose tissues [ 10 ].

These same β-3 adrenergic receptors are also associated with cardiovascular tissues, and their activation results in a down-regulation of cardiovascular stimulation [ 48 , 49 ].

Thus, p -synephrine stimulation of β-3 adrenoreceptors in the cardiovascular system does not result in an increase in blood pressure or heart rate but may exhibit a modulating rather than a stimulatory effect.

This cardiovascular receptor response may explain why an increase in heart rate or blood pressure is not seen in most cases when p -synephrine is used alone or in combination with caffeine in dietary supplements, in spite of the fact that caffeine alone may produce modest increases in these parameters under some conditions [ 50 , 51 ].

Approximately half of the clinical studies involved the use of commercial products. In only one case [ 28 ] was the actual amount of p -synephrine and other protoalkaloids determined, while in the remaining studies involving commercial products the reported amounts of p -synephrine and caffeine were simply based on label claim.

The amount of p -synephrine was independently determined in two studies in which bitter orange extract was used as a single ingredient product [ 36 , 37 ]. Various studies have shown that there are not always good correlations between the label claim of marketed products or the product data sheet and the amount of p -synephrine shown to be present by independent analysis [ 52 - 56 ].

Therefore, the actual amount of p -synephrine consumed in the majority of the studies was not verified. Finally, nine studies involving the administration of bitter orange extract alone or in combination with other constituents have demonstrated an increase in metabolic rate without an increase in heart rate or blood pressure [ 18 - 20 , 26 , 30 - 32 , 35 , 36 ].

These results suggest that bitter orange extract and p -synephrine may be beneficial in weight management. The results involving both published and unpublished clinical studies indicate that p -synephrine alone or in combination with caffeine does not appear to produce significant adverse cardiovascular effects or pose a risk to human health at doses commonly ingested orally.

No adverse effects have been directly attributable to bitter orange extract or p- synephrine. The results indicate that bitter orange extract and p -synephrine increase metabolism and energy expenditure.

The data accumulated to date do not support hypothesized concerns regarding potential adverse effects of p -synephrine particularly with respect to the cardiovascular system due to a paucity of binding to α-, β-1 and β-2 adrenergic receptors while exhibiting modest binding to β-3 adrenergic receptors.

All authors have served as consultants for Nutratech, Inc. Nutratech Inc. provided some of the unpublished research reports. Chen JK, Chen TT. Zhi Shi Fructus Aurantii Immaturus. Chinese Medical Herbology and Pharmacology. City of Industry, CA USA: Art of Medicine Press.

Stohs SJ, Shara M. A review of the safety and efficacy of Citrus aurantium in weight management. In: ed. Bagchi D, Preuss HG. Obesity: Epidemiology, Pathophysiology, and Prevention. Boca Raton, FL, USA: CRC Press.

Pellati F, Benvenuti S. Chromatographic and electrophoretic methods for the analysis of phenethylamine alkaloids in Citrus aurantium. J Chromatog A. Sander LC, Putzbach K, Nelson BC. et al. Certification of standard reference materials containing bitter orange.

Analyt Bioanalyt Chem. Evans RL, Pho AN, Roman MC, Betz JM. Penzak SR, Jann MW, Cold JA. Seville sour orange juice: synephrine content and cardiovascular effects in normotensive adults.

J Clin Pharmacol. Bent S, Padula A, Neuhaus J. Safety and efficacy of Citrus aurantium for weight loss. Amer J Cardiol. Nasir JM, Durning SJ.

Exercise-induced syncope associated with QT prolongation and ephedra-free Xenadrine. Mayo Clinic Proceed. Stephensen TA, Sarlay JrR. Ventricular fibrillation associated with use of a synephrine containing dietary supplement.

Military Med. Stohs SJ, Preuss HG, Shara M. A review of the receptor-binding properties of p -synephrine as related to its pharmacological effects. Oxid Med Cell Long.

Stohs SJ, Preuss HG. Stereochemical and pharmacological differences between naturally occurring p -synephrine and synthetic p -synephrine. J Funct Foods. McGuffin M. Media spins numbers on bitter orange AERs based on erroneous information from FDA.

The Safety of bitter orange Citrus aurantium and its primary protoalkaloid p -synephrine. The safety of Citrus aurantium bitter orange and its primary protoalkaloid p -synephrine. Phytother Res. Colker CM, Kalman DS, Torina GC, Perlis T, Street C. Effects of Citrus aurantium extract, caffeine, and St.

John's wort on body fat loss, lipid levels, and mood states in overweight healthy adults. Curr Therap Res. Dulloo AG, Duret C, Rohrer D. Efficacy of a green tea extract rich in catechin polyphenols and caffeine in increasing h energy expenditure and fat oxidation in humans.

Amer J ClinNutr. Kendall-Reed P. Study on the effectiveness of Ultra Slim Down ® for the reduction of body weight. Unpublished report. Kalman DS, Oxford S, Schwartz HI, Krieger DR. A double blind clinical evaluation of the metabolic effects of Xenadrine EFX TM compared to two ephedra-containing products in normal healthy volunteers.

Presented at the annual meeting of the American College of Nutrition, Abstract No. J Amer Coll Nutr. Kalman DS, Rubin S, Martinez T, Schwartz HI.

Presented at a meeting of NIH-National Institute of Diabetes and Digestive and Kidney Diseases. Kalman DS, Rubin S, Schwartz HI. An acute clinical trial to evaluate the safety and efficacy of a popular commercial weight loss supplement when used with exercise.

Presented at Federation of American Societies of Experimental Biology. Kalman DS, Colker CM, Shi Q, Swain MA. Effects of a weight-loss aid in healthy overweight adults: double-blind, placebo-controlled clinical study.

Curr Ther Res. Kalman DS, Incledon T, Gaunaurd I. An acute clinical trial evaluating the cardiovascular effects of an herbal ephedra-caffeine weight loss product in healthy overweight adults. Int J Obes. Kalman DS. Comment on: An acute clinical trial evaluating the cardiovascular effects of an herbal ephedra-caffeine weight loss product in healthy overweight adults.

Int J Obes Relat metab Disord. Gurley BJ, Gardner SF, Hubbard MA. In vivo assessment of botanical supplementation on human cytochrome P phenotypes: Citrus aurantium , Echinacea purpurea , milk thistle, and saw palmetto.

Clin Pharmacol Therap. Zenk JL, Kuskowski MA. Zenk JL, Leikam SA, Kassen LJ, Kuskowski MA. Effect of Lean System 7 on metabolic rate and body composition. Min B, Cios D, Kluger J, White CM. Absence of QTc interval- prolonging or hemodynamic effects of a single dose of bitter orange extract in healthy subjects.

Haller CA, Benowitz N, Peyton J III. Hemodynamic effects of ephedra-free weight loss supplements in humans. Amer J Med. Bui LT, Nguyen DT, Ambrose PJ. Blood pressure and heart rate affects following a single dose of bitter orange.

Ann Pharmacodyn. Sale C, Harris RC, Delves S, Corbett J. Metabolic and physiological effects of ingesting extracts of bitter orange, green tea and guarana at rest and during treadmill walking in overweight males.

Int J Obesity. Gougeon R, Harrigan K, Tremblay JF. Increase in the thermic effect of food in women by adrenergic amines extracted from Citrus aurantium. Obesity Res. Hoffman JR, Kang J, Ratamess A. Thermogenic effect from nutritionally enriched coffee consumption. J Int Soc Sports Nutr.

Citrus aurantium extract has no effect on blood pressure or heart rate in healthy adults. Unpublished report Talbott SM, Christopulos AM, Richards E.

Haller CA, Duan M, Peyton J III, Benowitz N. Human pharmacology of a performance-enhancing dietary supplement under resting and exercise conditions.

Brit J Clin Pharmacol. Seifert JG, Nelson A, Devonish J. Effect of acute administration of an herbal preparation on blood pressure and heart rate in humans. International J Med Sci. Stohs SJ, Preuss HG, Keith SC.

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. Shara M, Stohs SJ. Safety evaluation of bitter orange extract p -synephrine in healthy volunteers.

Presented at the annual meeting of the American College of Nutrition. Abstract No. Bloomer RJ, Canale RE, Blankenship MM. Effects of the dietary supplement Meltdown on catecholamine secretion, markers of lipolysis, and metabolic rate in men and women: a randomized, placebo controlled, cross-over study.

Lipids Health Disease. Bloomer R, Fisher-Wellman KH, Hammond KG. Dietary supplement increases plasma norepinephrine, lipolysis, and metabolic rate in resistance trained men. Hoffman JR, Kang J, Ratamess NA. Thermogenic effect of an acute ingestion of a weight loss supplement.

Stohs SJ. Athletic Benefits of Citrus Aurantium: Since ephedrine has been banned in sports, synephrine — containing citrus aurantium may be a good alternative.

The potential athletic benefits are as follows: May improve athletic performance by acting as a mild stimulant. Promotes mental clarity. Helps promote athletic agility. Useful in weight loss by decreasing appetite and increasing basal metabolic rate BMR.

Non — Athletic Benefits of Citrus Aurantium: Citrus aurantium may be beneficial in the following conditions: Gastrointestinal discomforts, such indigestion, constipation, and abdominal pain.

Weight management. Loss of appetite. Citrus Aurantium Triple Paradox: Depending on whether you take extracts of the leaves or peels of the immature or mature fruits, citrus aurantium shows three paradox effects: It may increase appetite, while it could suppress appetite due to a high amount of pectin.

It acts as a mild stimulant, while it has been used as a sedative in insomnia as well. While some has used it for high blood pressure, it actually increases blood pressure.

Contraindications: Citrus aurantium should be avoided in the following conditions: People with high blood pressure. People with depression who take the medications MAO inhibitors. Citrus aurantium contains tyramine that interacts with MAO inhibitors, leading to hypertensive crisis a sudden increase in blood pressure.

Heart diseases. Along with statins, the cholesterol — lowering medications. Pregnancy and breastfeeding. Peripheral artery disease. Diabetic vascular involvement. f Share.

A total of 23 published and unpublished studies involving a total of approximately total human subjects were reviewed. The authors located information regarding the unpublished studies through presentations at scientific meetings and availability of research reports on the internet, as well as information from the investigators involved in the studies.

Seven of the studies were not published in peer reviewed journals [ 17 - 20 , 25 , 33 , 37 ] Table 2. However, six of these studies were presented at national meetings [ 18 - 20 , 25 , 33 , 37 ], and one of these six studies is in the process of being submitted for consideration for publication [ 37 ].

As noted in the references, information including presentations and final reports are available on the internet regarding these unpublished studies. The results associated with these unpublished studies Table 2 in general are consistent with the results of the published studies Table 1.

Five published studies [ 6 , 24 , 27 , 31 , 36 ] and two unpublished studies [ 33 , 37 ] reported no cardiovascular effects when using p -synephrine bitter orange only containing products.

The published studies involved a total of subjects with a total of 31 subjects in the two unpublished studies. However, in one of these studies [ 24 ] consisting of 12 subjects it is not clear that effects on heart rate and blood pressure were specifically examined, with the authors simply reporting that no adverse effects were observed.

Five published studies [ 15 , 21 , 22 , 26 , 30 , 35 ] using p -synephrine in combination with other ingredients reported no cardiovascular effects. A total of 88 subjects were involved in these studies.

Small cardiovascular effects were reported by Bui et al. Small cardiovascular effects were reported for three studies that involved subjects consuming p -synephrine plus caffeine [ 28 , 32 , 34 ].

reported an increase in heart rate [ 28 ] and diastolic blood pressure [ 34 ] 10 subjects. Upon careful review, the study of Haller et al. p -Synephrine Advantra Z ® alone had no effect on systolic or diastolic blood pressure.

The authors reported an increase in heart rate six hours after treatment. The half-life of p -synephrine is two to three hours [ 28 , 34 , 45 ].

As a consequence, an increase in heart rate after two to three half-lives when the p- synephrine blood levels will have dropped to one-fourth to one-eighth the peak blood levels would not be expected. Furthermore, a major complicating factor is that all subjects consumed a meal three hours after ingesting the p -synephrine The cardiovascular and thermic effects of food are well known [ 31 ], and an increase in heart rate in the control group was also observed.

Thus, it is not plausible to attribute the increase in heart rate to p -synephrine, or an increase in heart rate and blood pressure to a product that contained very little p -synephrine 5.

This study did show that the commercial product Xenadrine EFX® which contained only 5. This product was reported to also contain 5. aurantium extracts are either devoid of octopamine or contain only trace amounts [ 3 ], thus the product being used [ 28 ] appears to have been adulterated.

Hansen et al. These doses represent over 13 times the usual daily dose for p -synephrine and the equivalent of the caffeine in about three cups of coffee given together as a single bolus dose to these animals.

When caffeine was added, increases in heart rate and blood pressure were observed [ 46 ]. These studies indicate that in rats at very high doses of p -synephrine the combination with caffeine may result in cardiovascular effects.

However, due to the highly inequivalent dosing between this study in rats and typical dosing in humans, the results of this study in rats cannot be directly extrapolated to humans.

A dose of 3. Various studies indicate that the lipolytic activity of p -synephrine is due to binding to β-3 adrenergic receptors in adipose tissues [ 10 ]. These same β-3 adrenergic receptors are also associated with cardiovascular tissues, and their activation results in a down-regulation of cardiovascular stimulation [ 48 , 49 ].

Thus, p -synephrine stimulation of β-3 adrenoreceptors in the cardiovascular system does not result in an increase in blood pressure or heart rate but may exhibit a modulating rather than a stimulatory effect. This cardiovascular receptor response may explain why an increase in heart rate or blood pressure is not seen in most cases when p -synephrine is used alone or in combination with caffeine in dietary supplements, in spite of the fact that caffeine alone may produce modest increases in these parameters under some conditions [ 50 , 51 ].

Approximately half of the clinical studies involved the use of commercial products. In only one case [ 28 ] was the actual amount of p -synephrine and other protoalkaloids determined, while in the remaining studies involving commercial products the reported amounts of p -synephrine and caffeine were simply based on label claim.

The amount of p -synephrine was independently determined in two studies in which bitter orange extract was used as a single ingredient product [ 36 , 37 ].

Various studies have shown that there are not always good correlations between the label claim of marketed products or the product data sheet and the amount of p -synephrine shown to be present by independent analysis [ 52 - 56 ]. Therefore, the actual amount of p -synephrine consumed in the majority of the studies was not verified.

Finally, nine studies involving the administration of bitter orange extract alone or in combination with other constituents have demonstrated an increase in metabolic rate without an increase in heart rate or blood pressure [ 18 - 20 , 26 , 30 - 32 , 35 , 36 ].

These results suggest that bitter orange extract and p -synephrine may be beneficial in weight management. The results involving both published and unpublished clinical studies indicate that p -synephrine alone or in combination with caffeine does not appear to produce significant adverse cardiovascular effects or pose a risk to human health at doses commonly ingested orally.

No adverse effects have been directly attributable to bitter orange extract or p- synephrine. The results indicate that bitter orange extract and p -synephrine increase metabolism and energy expenditure. The data accumulated to date do not support hypothesized concerns regarding potential adverse effects of p -synephrine particularly with respect to the cardiovascular system due to a paucity of binding to α-, β-1 and β-2 adrenergic receptors while exhibiting modest binding to β-3 adrenergic receptors.

All authors have served as consultants for Nutratech, Inc. Nutratech Inc. provided some of the unpublished research reports. Chen JK, Chen TT. Zhi Shi Fructus Aurantii Immaturus. Chinese Medical Herbology and Pharmacology. City of Industry, CA USA: Art of Medicine Press. Stohs SJ, Shara M. A review of the safety and efficacy of Citrus aurantium in weight management.

In: ed. Bagchi D, Preuss HG. Obesity: Epidemiology, Pathophysiology, and Prevention. Boca Raton, FL, USA: CRC Press. Pellati F, Benvenuti S. Chromatographic and electrophoretic methods for the analysis of phenethylamine alkaloids in Citrus aurantium.

J Chromatog A. Sander LC, Putzbach K, Nelson BC. et al. Certification of standard reference materials containing bitter orange. Analyt Bioanalyt Chem. Evans RL, Pho AN, Roman MC, Betz JM. Penzak SR, Jann MW, Cold JA. Seville sour orange juice: synephrine content and cardiovascular effects in normotensive adults.

J Clin Pharmacol. Bent S, Padula A, Neuhaus J. Safety and efficacy of Citrus aurantium for weight loss. Amer J Cardiol. Nasir JM, Durning SJ. Exercise-induced syncope associated with QT prolongation and ephedra-free Xenadrine.

Mayo Clinic Proceed. Stephensen TA, Sarlay JrR. Ventricular fibrillation associated with use of a synephrine containing dietary supplement. Military Med. Stohs SJ, Preuss HG, Shara M. A review of the receptor-binding properties of p -synephrine as related to its pharmacological effects.

Oxid Med Cell Long. Stohs SJ, Preuss HG. Stereochemical and pharmacological differences between naturally occurring p -synephrine and synthetic p -synephrine. J Funct Foods. McGuffin M. Media spins numbers on bitter orange AERs based on erroneous information from FDA.

The Safety of bitter orange Citrus aurantium and its primary protoalkaloid p -synephrine. The safety of Citrus aurantium bitter orange and its primary protoalkaloid p -synephrine. Phytother Res. Colker CM, Kalman DS, Torina GC, Perlis T, Street C.

Effects of Citrus aurantium extract, caffeine, and St. John's wort on body fat loss, lipid levels, and mood states in overweight healthy adults. Curr Therap Res. Dulloo AG, Duret C, Rohrer D. Efficacy of a green tea extract rich in catechin polyphenols and caffeine in increasing h energy expenditure and fat oxidation in humans.

Amer J ClinNutr. Kendall-Reed P. Study on the effectiveness of Ultra Slim Down ® for the reduction of body weight. Unpublished report. Kalman DS, Oxford S, Schwartz HI, Krieger DR. A double blind clinical evaluation of the metabolic effects of Xenadrine EFX TM compared to two ephedra-containing products in normal healthy volunteers.

Presented at the annual meeting of the American College of Nutrition, Abstract No. J Amer Coll Nutr. Kalman DS, Rubin S, Martinez T, Schwartz HI. Presented at a meeting of NIH-National Institute of Diabetes and Digestive and Kidney Diseases. Kalman DS, Rubin S, Schwartz HI.

An acute clinical trial to evaluate the safety and efficacy of a popular commercial weight loss supplement when used with exercise. Presented at Federation of American Societies of Experimental Biology.

Kalman DS, Colker CM, Shi Q, Swain MA. Effects of a weight-loss aid in healthy overweight adults: double-blind, placebo-controlled clinical study.

Curr Ther Res. Kalman DS, Incledon T, Gaunaurd I. An acute clinical trial evaluating the cardiovascular effects of an herbal ephedra-caffeine weight loss product in healthy overweight adults. Int J Obes. Kalman DS. Comment on: An acute clinical trial evaluating the cardiovascular effects of an herbal ephedra-caffeine weight loss product in healthy overweight adults.

Int J Obes Relat metab Disord. Gurley BJ, Gardner SF, Hubbard MA. In vivo assessment of botanical supplementation on human cytochrome P phenotypes: Citrus aurantium , Echinacea purpurea , milk thistle, and saw palmetto.

Clin Pharmacol Therap. Zenk JL, Kuskowski MA. Zenk JL, Leikam SA, Kassen LJ, Kuskowski MA. Effect of Lean System 7 on metabolic rate and body composition. Min B, Cios D, Kluger J, White CM. Absence of QTc interval- prolonging or hemodynamic effects of a single dose of bitter orange extract in healthy subjects.

Haller CA, Benowitz N, Peyton J III. Hemodynamic effects of ephedra-free weight loss supplements in humans.

Amer J Med. Bui LT, Nguyen DT, Ambrose PJ. Blood pressure and heart rate affects following a single dose of bitter orange. Ann Pharmacodyn. Sale C, Harris RC, Delves S, Corbett J.

Metabolic and physiological effects of ingesting extracts of bitter orange, green tea and guarana at rest and during treadmill walking in overweight males. Int J Obesity. Gougeon R, Harrigan K, Tremblay JF. Increase in the thermic effect of food in women by adrenergic amines extracted from Citrus aurantium.

Obesity Res. Hoffman JR, Kang J, Ratamess A. Thermogenic effect from nutritionally enriched coffee consumption. J Int Soc Sports Nutr. Citrus aurantium extract has no effect on blood pressure or heart rate in healthy adults.

Unpublished report Talbott SM, Christopulos AM, Richards E. Haller CA, Duan M, Peyton J III, Benowitz N. Human pharmacology of a performance-enhancing dietary supplement under resting and exercise conditions.

Brit J Clin Pharmacol. Seifert JG, Nelson A, Devonish J. Effect of acute administration of an herbal preparation on blood pressure and heart rate in humans. International J Med Sci.

Stohs SJ, Preuss HG, Keith SC. 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. Shara M, Stohs SJ. Safety evaluation of bitter orange extract p -synephrine in healthy volunteers. Presented at the annual meeting of the American College of Nutrition. Abstract No. Bloomer RJ, Canale RE, Blankenship MM.

Effects of the dietary supplement Meltdown on catecholamine secretion, markers of lipolysis, and metabolic rate in men and women: a randomized, placebo controlled, cross-over study. Lipids Health Disease.

Bloomer R, Fisher-Wellman KH, Hammond KG. Dietary supplement increases plasma norepinephrine, lipolysis, and metabolic rate in resistance trained men. Hoffman JR, Kang J, Ratamess NA. Thermogenic effect of an acute ingestion of a weight loss supplement.

Stohs SJ. Assessment of the adverse event reports associated with Citrus aurantium bitter orange from April to October Dragull K, Breksa AP, Cain B. Synephrine content of juice from Satsuma mandarins Citrus unshiu Marcovitch. J Agric Food Chem. Uckoo RM, Jayaprakasha GK, Nelson DS, Pati BS.

Rapid simultaneous determinations of amines and organic acids in citrus using high-performance liquid chromatography. Karch SB. Peer review and the process of publishing of adverse drug event reports. J Forensic Legal Med. Hengtmann JH, Aulepp H.

Pharmacokinetics and metabolism of synephrinc. Arzneimittel Forschung. Hansen DK, George NI, White GE. Physiological effects following administration of Citrus aurantium for 28 days in rats. Toxicol Appl Pharmacol.

Reagan-Shaw S, Nihal M, Ahmed N. Dose translation from animal to human studies revisited. FASEB J. Rozec B, Gauther C. β3-Adrenoreceptors in the cardiovascular system: Putative roles in human pathologies.

Pharmacol Therap. Moens AL, Yang R, Watts V, Barouch LA. Beta 3-adrenoreceptor regulation of nitric oxide in the cardiovascular system.

J Molec Cell Cardiol. Yang A, Palmer AA, DeWit H. Genetics of caffeine consumption and responses to caffeine. Riksen NP, Smits P, Rongen GA. The cardiovascular effects of methylxanthines. Handbook Exper Pharmacol. Avula B, Upparapalli SK, Navarrete A, Khan IA. Simultaneous quantification of adrenergic amines and flavonoids in C.

aurantium , various Citrus species, and dietary supplements by liquid chromatography. J AOAC Int. Slezak T, Francis PS, Anastos N, Barnett NW. Determination of synephrine in weight-loss products using high performance liquid chromatography with acidic potassium permanganate chemiluminescence detection.

Anal Chim Acta. Evans LE, Siitonen PH. Determination of caffeine and sympathomimetic alkaloids in weight loss supplements by high-performance liquid chromatography.

J Chromatog Sci. Mercolini L, Mandrioli R. Fast CE analysis of adrenergic amines in different parts of Citrus aurantium fruit and dietary supplements. J Sep Sci. Percy DW, Adcock JL, Conlan XA. Determination of Citrus aurantium protoalkaloids using HPLC with potassium permanganate chemiluminescence detection.

Corresponding author: Harry G. Terms of use. Impact factor 3. Home Author info Editorial board Submit manuscript Manuscript login Contact . Top Introduction Human Studies Clinical Case Reports Discussion Summary and Conclusions Acknowledgements References.

Theranostics International Journal of Biological Sciences Nanotheranostics Journal of Cancer Journal of Genomics Global reach, higher impact. Citation: Stohs SJ, Preuss HG, Shara M. A Review of the Human Clinical Studies Involving Citrus aurantium Bitter Orange Extract and its Primary Protoalkaloid p- Synephrine.

Fig 1 Chemical structure of p -synephrine. Fig 2 Chemical structure of m -synephrine. Fig 3 Chemical structure of ephedrine.

Antioxidants are substances that may protect your body from disease by preventing cell damage. They work by deactivating free radicals, which are unstable compounds that damage your cells, increasing inflammation and your disease risk 15 , Protoalkaloids are plant compounds found in bitter orange that have anti-inflammatory and antiviral properties.

They have been shown to be safe for consumption. Many weight loss supplements use bitter orange extracts in combination with other ingredients. However, scientific studies have not thoroughly examined the composition of these supplements to determine which ingredient, if any, supports weight loss.

Notably, p-synephrine has been shown to increase fat breakdown, raise energy expenditure, and mildly suppress appetite , all of which may contribute to reduced weight. Yet, these effects occur at high doses that are discouraged due to the lack of safety information 4 , 8 , Bitter orange and its extracts are used in Traditional Chinese Medicine TCM to treat indigestion, diarrhea, dysentery, and constipation.

In other regions, the fruit is used to treat anxiety and epilepsy 3. Another study noted that the bitter orange compound p-synephrine may improve athletic performance though by increasing total reps and volume load, or your ability to train harder A stimulant is a substance that increases your heart rate and blood pressure 1.

Several sports organizations, such as the National Collegiate Athletic Association NCAA , list synephrine as a stimulant.

Furthermore, one study determined that bitter orange juice contains furanocoumarin, a compound that may cause the same medication interactions as grapefruit juice Therefore, people taking decongestants or those who have high blood pressure, an irregular heartbeat, or glaucoma should avoid the juice and fruit of bitter oranges.

Despite numerous studies showing that bitter orange extracts are not stimulants, widespread controversy exists, and the NCAA has listed it as a banned substance.

Bitter orange may also interact with certain medications. Generally, bitter orange extracts in dietary supplements are safe to consume in doses of 50—98 mg per day 1 , One study showed that 40 mg of synephrine combined with mg of caffeine is a safe dose of these combined ingredients 3.

In another study, eating a whole bitter orange containing Still, people who are pregnant or breastfeeding should avoid bitter orange due to a lack of safety information 1. Bitter orange is likely safe in doses ranging from The juice of the bitter orange can be used as a marinade to flavor fish and meat.

Bitter orange has several other household uses outside of the kitchen. These include 2 :. Bitter orange is a citrus fruit with several household and industrial uses, ranging from food additives to perfumery.

You may want to avoid this fruit and its extracts if you have high blood pressure, an irregular heartbeat, or glaucoma. Likewise, bitter orange supplements are banned for NCAA athletes.

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Here's why. A Quiz for Teens Are You a Workaholic? How Well Do You Sleep? Health Conditions Discover Plan Connect. Nutrition Evidence Based What Is Bitter Orange, and Does It Aid Weight Loss?