Citrus aurantium health -
Preuss, M. This review summarizes the published as well as unpublished human studies involving Citrus aurantium bitter orange extract and its primary protoalkaloid p -synephrine, providing information and an assessment of the safety and efficacy of these widely used products.
The results of over 20 studies involving a total of approximately subjects that consumed p -synephrine alone or in combination with other ingredients are reviewed and critiqued. In general, bitter orange extract alone p -synephrine or in combination with other herbal ingredients did not produce significant adverse events as an increase in heart rate or blood pressure, or alter electrocardiographic data, serum chemistry, blood cell counts or urinalysis.
Longer term studies are needed to further assess the efficacy of these products and affirm their safety under these conditions. Citrus aurantium extract and its primary protoalkaloidal constituent p -synephrine Figure 1 are extensively used in weight management products and as thermogenic agents.
They are also used in sports performance products to enhance stamina. aurantium extract is widely known as bitter orange extract, a product that is derived from the immature green fruits of the Seville orange. Bitter orange extract is used in weight management products due to its purported effects on metabolic processes, including an increase in basal metabolic rate and lipolysis as well as mild appetite suppression [ 2 ].
Uncertainty has existed concerning the safety of bitter orange extract and p -synephrine. In general, both the lay public and scientific communities have failed to differentiate between p- synephrine which is a phenylethylamine derivative that has the hydroxy group in the para position on the benzene ring and the synthetic m -synephrine phenylephrine which has a hydroxyl group in the meta position on the benzene ring Figure 2.
m -Synephrine exhibits cardiovascular effects but is not a constituent of bitter orange [ 3 - 5 ]. Properties possessed by m -synephrine are inappropriately attributed to bitter orange extract and p- synephrine, and clinical case study reports and reviews involving bitter orange extract frequently make inappropriate references to m -synpephrine see for example [ 6 - 9 ].
A limited number of studies have been conducted with p -synephrine and bitter orange extracts without the addition of various other ingredients and herbal products. The issue of safety and efficacy is further clouded and complicated by the structural similarity of p -synephrine to ephedrine Figure 3 and other biogenic amines, in spite of the fact that the pharmacokinetics of the these compounds and their receptor binding specificities are vastly different due to significant structural and stereochemical differences [ 10 , 11 ].
As a consequence, markedly different pharmacological properties should be anticipated. Other issues have also obfuscated the picture with respect to the safety and efficacy of bitter orange extract. Some of the extracts that are used are either non-standardized or poorly standardized, making it difficult if not impossible to establish reproducibility.
In some cases, lack of knowledge of the chemical composition of the extracts being used precludes useful comparisons. Products containing bitter orange extract in most cases contain a variety of other herbal extracts, many of which are caffeine containing. A final issue that has added to the overall confusion regarding bitter orange has been the release of erroneous adverse events information by governmental agencies.
Statements implying that large numbers of adverse events and even deaths due to the use of products containing bitter orange extract have clearly been shown to be incorrect and misleading [ 12 ], but are still widely reported.
Several reviews have addressed the safety of bitter orange extract based on animal, in vitro and receptor binding studies as well as some human studies [ 2 , 10 , 13 ].
This review addresses data associated with published human studies, clinical case reports, and unpublished clinical studies. Information with respect to unpublished studies is derived from final research reports available on the internet, presentations at national meetings of professional organizations, and presentations and research reports from the investigators directly involved.
References are cited based on the origin of the information. A limited number of well-designed and controlled human studies have been conducted with bitter orange extracts assessing efficacy and safety. The majority of studies have been conducted using products that contain not only an extract of C.
aurantium , but other ingredients such as caffeine, green tea, ginkgo, ginseng, guarana, and yerba mate'. The incorporation of bitter orange extract into products containing other potentially active ingredients makes comparative analyses difficult.
However, several human safety and efficacy studies have been conducted on bitter orange extract p -synephrine alone.
Colker et al. The product which was consumed on a daily basis contained mg C. John's wort. The total daily intake of phenylethylamine-related protoalkaloids was approximately After six weeks, the treated group lost small but significant amounts of body weight 1.
No significant changes in blood pressure, heart rate, electrocardiographic findings, serum chemistry or urinalysis were noted and no significant changes were observed in the results of the Profile of Mood States Questionnaire for fatigue or vigor.
The treated group also experienced a significant increase in basal metabolic rate as compared to the placebo group. The amount of caffeine consumed daily in the product mg is equivalent to approximately four cups of coffee or over five cups of tea, and is a well-known thermogenic agent [ 16 ].
It is not clear whether the weight loss and increase in basal metabolic rate were due to the caffeine, the bitter orange extract, exercise, caloric restriction or a combination thereof. This combination of ingredients and protocol appeared to be effective and safe for promoting modest fat and body weight loss in healthy, overweight adults, although the number of subjects in the study was small [ 15 ].
Kendall-Reed [ 17 ] conducted a 10 week unpublished study on a system Ultra Slim Down ® that consisted of two products Table 2. The final report of the study is available on line. One product contained mg hydroxycitric acid Citrimax TM , mg bitter orange extract Advantra Z ® and 50 mg kola nut extract, while the second product contained mg chitosan.
Thirty-two overweight subjects were divided into three groups and either given the two products one capsule of each in conjunction with each meal , a diet and exercise program, or the products in conjunction with the diet and exercise program.
At the end of the study no adverse side effects were observed or reported. The group consuming the product-only lost an average of 4. In summary, consumption of the products alone was more effective than diet and exercise, while consuming the products in combination with diet and exercise was most effective.
No adverse effects were reported. This study was not published and subjected to peer review. Possible cardiovascular effects of Seville sour orange juice in normotensive adults were assessed by Penzak et al. Twelve subjects consumed 8 ounces of orange juice approximately 13 mg p -synephrine and water in a crossover design followed by repeat ingestion 8 hours later.
Hemodynamic parameters including heart rate and blood pressure did not significantly differ between control and treated groups.
In spite of the lack of evidence, the authors concluded that individuals with tachyarrhythmias, severe hypertension and narrow angle glaucoma as well as monoamine oxidase inhibitor receptors should avoid Seville orange juice. The warning was based on the erroneous assumption that the form of synephrine present in the orange juice was m -synephrine [ 6 ].
Kalman and associates have conducted three unpublished studies using a commercial weight loss product Xenadrine EFX ® Table 2. The product contained a proprietary blend of extracts from C. aurantium bitter orange , yerba mate, grape seed, green tea and ginger root in addition to several vitamins and amino acids.
The product contained 6 mg p -synephrine, mg caffeine and mg catechin polyphenols in capsule form. The results of these studies were presented at various scientific meetings, but were never published in a scientific journal and subjected to peer review.
In each of these studies it is not possible to determine the role of p -synephrine in the observed effects. A double blind cross-over study involving 6 healthy human subjects who received two capsules of Xenadrine EFX ® 12 mg p -synephrine Kalman et al. A significant increase 2.
No effects on heart rate or blood pressure were observed, and no subjective complaints or adverse events were reported.
Kalman et al. Basal metabolic rates were determined at baseline, four hours after a standardized meal at which time two capsules of Xenadrine EFX ® or the placebo were ingested, and hourly for the next five hours. At the two and three hour time points after ingestion of the product relative to the control, No significant differences in heart rate or blood pressure were observed in response to the product relative to baseline and control values.
No significant effects of the product were noted as compared to the placebo group with respect to blood pressure, heart rate, electrocardiographic data, fasting blood glucose, renal function, hepatic function or complete blood count with differentials over the 14 days of the study.
The treated group experienced a significant reduction in fatigue levels, while sleep quality was negatively impacted. At the end of the study, the treated group experienced a reduction in diastolic blood pressure as compared to the placebo group The authors concluded that the product was safe over the course of the study [ 20 ].
No weight loss was observed over the two weeks of the study. Half of the subjects were randomly assigned to either the treatment or control group.
After 8 weeks the experimental group had lost a significantly greater amount of weight than the control group 3. The daily intake of p -synephrine 10 mg was small, and its relative contribution to the overall weight loss cannot be determined. The study was a 14 day, placebo-controlled double-blinded crossover protocol where subjects received two capsules of the product or placebo for the first seven days and four capsules per day for the next seven days.
Analyses were conducted at baseline, and days seven and No significant differences were observed at any time point between treated and placebo control with respect to systolic and diastolic blood pressures, heart rate, or heart valve function and left ventricular ejection fraction as determined by serial echocardiograms or Doppler echocardiograms.
The maximum amount of p -synephrine 10 mg per day was small compared to the maximum amounts of ephedrine 40 mg per day and caffeine mg per day. A statistically larger proportion of subjects taking the product reported minor adverse effects as dry mouth, increased activity, and sleep disorders, but there were no serious adverse events and no significant difference with regard to cardiovascular measurements heart rate, blood pressures, serial echocardiograms and Doppler echocardiograms between the treated and placebo groups.
Gurley et al. The daily consumption of p -synephrine was The authors concluded that a supplement containing C. aurantium extract did not appear to significantly modulate cytochrome P enzyme activities in human subjects, and therefore posed minimal risk for cytochrome Pmediated, herb-drug interactions.
The bitter orange extract had no significant effect on CYP1A2, CYP2D6, CYP2E1 or CYP3A4, the major drug-metabolizing cytochrome enzymes. No adverse effects were observed. The authors did not assess the possible effects on body weight or blood chemistry. The study was not published Table 2 , but a copy of the final report is available on line.
Of the 65 adults enrolled, 54 completed the study with 6 dropouts from the placebo group and 5 subjects from the product treatment group. The product contained extracts of bitter orange, guarana and green tea as well as 7-oxo-dehydroandrostenedione DHEA , conjugated linoleic acid and chromium picolinate.
The daily consumption of bitter orange extract was mg but the p -synephrine content was not noted. At the completion of the 8 week study, the treated group lost an average of 2. No significant differences occurred between the treatment and placebo groups with respect to systolic and diastolic blood pressures, heart rate or temperature.
Furthermore, there were no significant differences in serum chemistry profiles and complete blood counts between the two groups. There was also no difference in the reported incidence of adverse events between the two groups and no serious adverse events were reported [ 25 ].
It is not possible to determine the role of p- synephrine and the bitter orange extract in the observed effects. This was a randomized, double-blind placebo-controlled study involving healthy, overweight adults.
A total of 35 subjects completed the 8 week study. Each adult received three capsules of the weight-loss product twice daily or a placebo in conjunction with a calorie-restricted diet and an exercise program. The product also contained 3-acetyloxo-dehydroepiandrosterone 17 mg , Coleus forskohlli extract 50 mg extract, 10 mg forskolin , yerba mate extract mg , guarana extract mg extract, 51 mg caffeine , piperine 1.
The most significant finding of the study was a 7. No significant differences were noted between the treated and the placebo-controlled groups with respect to body weight, body fat, or lean tissue [ 26 ]. No changes in heart rate or blood pressure were observed and no serious adverse events were reported.
The relative role of each of the ingredients cannot be determined. Min et al. This randomized, placebo-controlled, double blind and crossover study involved 18 healthy subjects.
The rate-corrected QT QTc interval and blood pressure were measured before dosing and at 1, 3, 5 and 8 hrs after dosing. The bitter orange extract did not significantly alter the QTc interval or the systolic or diastolic blood pressures at any time point.
Haller et al. The protocol consisted of a randomized, double blind, placebo-controlled crossover design involving 10 subjects with a one-week washout between treatments.
The results showed that the dietary supplement but not the p- synephrine-containing bitter orange extract increased both systolic and diastolic blood pressures at two hours post-treatment, while heart rate increased at six hours by The authors concluded that the pressure effects were not likely caused by the C.
aurantium alone since no blood pressure effect was observed with an 8-fold higher dose of p -synephrine. The authors also concluded that the increase in blood pressure may be attributable to caffeine and other stimulants in the dietary supplement. The increase in heart rate reported for p -synephrine at 6 hours is not consistent with the pharmacokinetics of p- synephrine or a number of other studies, and is discussed in detail below.
The amounts of the ingredients in the products were verified by analytical analysis. Bui et al. Heart rate and blood pressure were measured every hour for six hours. These investigators reported small but clinically insignificant increases in heart rate, and systolic and diastolic blood pressures for up to five hours.
The difference in the results between this study and the study of Min et al. However, these effects on heart rate and blood pressure were small and have not been observed in other studies.
Sale et al. As noted above, this product contained bitter orange, guarana and green tea extracts. Subjects received either the placebo or the product and were followed for seven hours or exercised on a treadmill for 60 min. The product had no effect on ATP utilization under resting or exercise conditions relative to control.
Fatty acid oxidation to ATP decreased while plasma levels of fatty acids increased in response to the product. The product had no effect on resting heart rate or blood pressure.
Gougeon et al. No other ingredients were present in the product. The thermic effect of food on a 1. Five capsules of the C. aurantium extract provided 26 mg p -synephrine, and 4 mg or less each of other phenethylamines Advantra Z ®. The thermic effect of food was determined on an initial 30 subjects.
A subset of 11 men and 11 women were additionally studied after ingestion of the bitter orange extract in conjunction with the protein meal, while a another subset of 12 women and 8 men were studied a third time following ingestion of the C.
aurantium -containing capsules alone. The thermic effect of the bitter orange extract was greater in men than women in the absence of a meal.
A significant increase in the respiratory quotient occurred in both sexes in response to the bitter orange extract alone. No significant changes occurred in systolic and diastolic blood pressures or pulse rates when compared with base line values following exposure to the bitter orange extract.
Hoffman et al. aurantium extract, Garcinia cambogia and chromium JavaFit TM over a three hour period of time in a randomized, double blind study which involved 10 healthy, physically active subjects Table 1.
The enriched coffee product contained mg caffeine, Significant increases were observed in responders with respect to resting metabolic rate and respiratory exchange ratio. No significant differences were observed in average heart rate or diastolic blood pressure while a 3 mm Hg increase was observed in the systolic blood pressure.
The modest effect on blood pressure is not surprising based on the amount of caffeine in the product. Talbott et al. 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 ]. While some research suggests that bitter orange Citrus aurantium can help with modest weight loss when combined with diet and exercise, it's probably not worth the risk. That's because bitter orange may cause potentially serious health problems.
So if you're trying to lose weight, stick to healthier methods and skip the bitter orange. Bitter orange extract is often used in weight-loss supplements.
Bitter orange contains synephrine, which is similar to the main chemical in the herb ephedra ma-huang. Ephedra was banned by the U.
Food and Drug Administration because it raises blood pressure and has been linked to heart attacks and strokes. Like ephedra, synephrine may speed up your heart rate and raise your blood pressure. Strokes and heart attacks have been reported in some people after taking bitter orange alone or in with other stimulants such as caffeine.
Amino acid synthesis in plants Orange zhi shi, Ginger tea recipealso known auarntium Immature Orange FruitCitrus AurantiumSeville Orange Cutrus Sour Orangeis a sour citrus fruit Ctirus is a common main ingredient in Orange Marmalade. Amino acid synthesis in plants to East Citruus, Citrus aurantium health Strengthening immune system function Peninsula, Syria, and Southeast Asia, Bitter Orange is one of the most tart and pungent citrus fruits in the world. During the Middle Ages, Bitter Orange became a favourite in the Middle East and was highly respected by Arabian physicians. During the 16th Century, it was said that an Italian princess named Anna-Marie de Nerola extracted oil from the flowers of this plant to scent her gloves. Till today, this floral oil is still used in perfumes and essential oils. An invaluable therapeutic herb, Bitter Orange is also applauded for its medicinal usages, which are commonly used in Traditional Chinese Medicine TCM. Background: There are still no studies of the cardiovascular Citus of the isolated Amino acid synthesis in plants of Citrus aurantium aurxntium aerobic submaximal exercise. Objective: To jealth Amino acid synthesis in plants effect of C. aurantium Beetroot juice for detoxification on the recovery of cardiorespiratory and autonomic parameters following a session of submaximal aerobic exercise. Methods: Twelve healthy male adults achieved a crossover, randomized, double-blind, and placebo-controlled trial. We evaluated systolic blood pressure SBPdiastolic blood pressure DBPpulse pressure PPmean arterial pressure MAPheart rate HR and, HR variability indexes at Rest and during 60 min of recovery from exercise.
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