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Advantra Z Toxicity



The single-dose oral toxicity of Advantra Z® was evaluated in Sprague-Dawley rats. A limit test was performed in which one group of five male and five female rats received a single oral administration of the test article at a dose of 10000 mg/kg body weight Following dosing, the limit test rats were observed daily and weighed weekly. A gross necropsy examination was performed on all limit test animals at the time of scheduled euthanasia (day 14). No mortality occurred during the limit test, the most notable clinical abnormalities observed during the study included rough coat, decreased activity, congested breathing, dark material around the facial area, decreased defecation, salivation, soft stools and urine/fecal stain.

These clinical abnormalities were observed during the first few days after dosing, but then disappeared, with the exception of residual slight hair loss which was still present in one animal for 14 days and in another after 7 days. A slight body weight loss was noted for one female rat during the study day 7-14 body weight interval. However, since the animals were young adults and still growing, body weight gain was noted for all other animals during the test period. No significant gross internal findings were observed at necropsy on study day 14. Under the conditions of this test, the acute oral LD50 of Advantra Z® was estimated to be greater than 10000 mg/kg in the rat. SLI Study No. 3443.1 (6)


This study was performed to assess the short-term toxicity of Advantra Z® in Sprague-Dawley rats when administered by gavage as a single oral dose. This study is intended to provide information on the potential health hazards of the test article with respect to oral exposure. Data from this study may serve as a basis for classification and/or labeling of the test article. This study was performed at Springborn Laboratories, Inc., 553 North Broadway, Spencerville, Ohio. The protocol was signed by the Study Director on February 28, 1997 (GLP initiation date). The in-life phase of the study was initiated with test article administration on March 13, 1997 and concluded with terminal euthanasia on March 27, 1997.


A. Test Article

The test article was received from the Sponsor and identified as follows: The test article was stored at room temperature. The Sponsor is responsible for any necessary evaluations related to identity, strength, purity, composition, stability and method of synthesis of the test material according to 21 CFR 58.105.

B. Retention Sample

The Sponsor was responsible for maintaining a retention sample of the test article.

C. Test Article Disposition

The remaining test article was returned to the Sponsor following completion of all studies with the test article.

D. Method of Test Article Preparation

The test article was mixed with demonized water to produce the appropriate concentration for dose administration.

E. Animals and Animal Husbandry

1. Description, Identification and Housing

Young adult, Sprague-Dawley Crl:CD®BR VAF/PIus® rats were received at SLI from Charles River Laboratories, Inc-, Portage, Michigan_ The animals were approximately 8-13 weeks of age at experimental initiation. Upon receipt, metal ear tags displaying unique identification numbers were used to individually identify the animals. Cage cards displaying at least the study number, animal number and sex were affixed to each cage. The animals were housed individually in suspended stainless steel rages. All housing and care were based on the standards recommended by the Guide for the Care and Use of Laboratory Animals [1).

2. Environment

The animal room temperature and relative humidity ranges were 68-74°F and 30-53%, respectively. Environmental control equipment was monitored and adjusted as necessary to minimize fluctuations in the animal room environment Light timers were set to maintain a 12-hour light/I2 -hour dark cycle and room ventilation was set to produce 10-15 air changes/hour. The animal room temperature and relative humidity were recorded a minimum of once daily.

3. Food

PM! Certified Rodent. Chow #5002 (Purina Mills, Inc.) was provided ad libitum to the animals throughout the study (except during fasting). The lot number and expiration date of each batch of diet used during the study were recorded. The feed was analyzed and certified by the supplier for nutritional components and environmental contaminants_ Dietary limitations for various environmental contaminants, including heavy metals, pesticides, polychlorinated biphenyls and total aflatoxin are set by the manufacturer. Within these limits, contaminants which may have been present were not expected to compromise the purpose of this study. Results of the dietary a nalyses (Certificates of Analysis) are provided by the manufacturer for each lot of diet. These are maintained by SLI

4. Water

Municipal tap water treated by reverse osmosis was available ad libitum throughout the study. The purified water was supplied by an automatic watering system. Monitoring of the drinking water for contaminants is conducted annually by SLI and the records are available for inspection. Within generally accepted limits, contaminants which may have been present were not expected to compromise the purpose of this study. The water meets the standards specified under the EPA National Drinking Water Regulations (40 CFR, Part 141).

5. Acclimation

Upon receipt the animals were removed randomly from the shipping cartons, examined by qualified personnel, identified with metal ear tags and then acclimated to the laboratory conditions for a minimum of five days. The animals were observed daily for overt physical or behavioral abnormalities, general health/moribundity and mortality.

6. Animal Selection

The animals chosen for study use were arbitrarily selected from healthy stock animals to avoid potential bias. All animals received a detailed pretest observation prior to dosing. Only healthy animals were chosen for study use. Females were nulliparous and nonpregnant.


A. Dosing

On day-1, the animals chosen for the limit test were weighed and fasted overnight On day 0, the test article was administered orally as a single dose using a ball tipped stainless steel gavage needle attached to a syringe at the following level: Individual doses were calculated based on the animal’s fasted (day 0) body weight Animals were returned to ad libitum feeding after dosing.

Dose Level Dose Volume Concentration No. of Animals
(mg/kg) (mL/kg) (mg/mL) Males Females
10000 20 500 5 5

B. Clinical Observations

Limit test animals were observed for clinical abnormalities two times on study day 0 (postdose) and daily thereafter (days 1-14). A general health/mortality check was performed twice daily (in the morning and in the afternoon).

C. Body Weights

Individual body weights were obtained for the limit test animals prior to fasting (day -1), prior to dosing on day 0 and on days 7 and 14.

D. Gross Necropsy

All limit test animals were euthanized by carbon dioxide inhalation at study termination (day 14) and necropsied. Body cavities (cranial, thoracic, abdominal and pelvic) were opened and examined. No tissues were retained.

E. Protocol Deviations

No protocol deviations occurred during this study.


Data from the limit test were analyzed and an LD50 value estimated as follows:

  • < 50% Mortality: LD50 was estimated as greater than the administered dose.
  • = 50% Mortality: LD50 was estimated as equal to the administered dose.
  • > 50% Mortality: LD50 was estimated as less than the administered dose.

Body weight means and standard deviations were calculated separately for males and females for each limit level administered.


All original paper data, the final report and magnetically encoded records were transferred to the SLI archives for a period of 10 years. The Sponsor will be contacted prior to final disposition of these items.


A. Mortality

No mortality occurred during the limit test

B. Clinical Observations Individual Data: Table 1

The most notable clinical abnormalities observed during the study included rough coat, decreased activity, congested breathing, dark material around the facial area, decreased defecation, salivation, soft stools and urine/fecal stain. These clinical abnormalities were observed during the first few days after dosing, but then disappeared, with the exception of residual slight hair loss which was still present in one animal for 14 days and in another after 7 days.

C. Body Weight Data Individual Data: Table 2

A slight body weight loss was noted for one female rat during the study day 7-14 body weight interval. Normal body weight gain resumed for all other animals during the test period.

D. Gross Necropsy

No significant gross internal findings were observed at necropsy on study day 14.


Under the conditions of thus test, the acute oral LD50 of Advantra Z® was estimated to be greater than 10000 mg/kg in the rat Deborah A. Douds, M.S. Study Director


Todd N. Merriman, B.S., LATG
Manager of Subchronic Toxicology
Kimberly L Bonnette, M.S., LATG
Manager of Acute Toxicology


  1. Guide for the Care and Use of Laboratory Animals, DHHS Publication No. (NIH) 96-03,1996.

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Ephedra Free Weight Loss


Hemodynamic effects of ephedra-free weight-loss supplements in humans

Christine A. Haller, MD, Neal L. Benowitz, MD, Peyton Jacob III, PhD

Division of Clinical Pharmacology and Experimental Therapeutics, Department of Medicine, University of California, San Francisco.

ABSTRACT PURPOSE: Ephedra-free weight loss dietary supplements containing bitter orange (Citrus aurantium), a botanical source of the adrenergic amines synephrine and octopamine, have quickly emerged on consumer markets to replace banned ephedra products. These supplements may have some of the health risks associated with ephedra, but studies in humans are lacking. Our aim was to characterize the pharmacokinetics and cardiovascular effects of C. aurantium dietary supplements.

SUBJECTS AND METHODS: Ten healthy adult nonsmokers participated in a randomized, doubleblind, placebo-controlled, three-arm crossover study. Single doses of C. aurantium (Advantra Z) containing 46.9 mg synephrine, Xenadrine EFX, a multi-component formulation containing 5.5 mg synephrine, and placebo were administered with a one-week washout.

RESULTS: Compared with placebo, Xenadrine EFX but not Advantra Z increased systolic and diastolic blood pressure with peak changes from baseline at 2 hours of 9.6 _ 6.2 mm Hg systolic (P _ 0.047), and 9.1 _ 7.8 mm Hg diastolic (P _ 0.002). Heart rate was increased from baseline at 6 hours compared with placebo (16.7 beats per minute with Xenadrine EFX, P _ 0.011; 11.4 beats per minute with Advantra Z, P _ 0.031). Dose-adjusted synephrine pharmacokinetics were similar between treatments with tmax _ 90 min, t1/2 _ 3.0 hours, V/F _ 16347 L, and CL/F _ 88.9 L/min for Xenadrine EFX.

CONCLUSION: Ephedra-free weight loss supplements have significant cardiovascular stimulant actions, similar to ephedra. These effects are not likely caused by C. aurantium alone, because an eightfold higher dose of synephrine (Advantra Z) had no effect on blood pressure, but may be attributable to caffeine and other stimulants in the multi-component formulation 2005 Elsevier Inc. All rights reserved.

Weight loss dietary supplements containing bitter orange (Citrus aurantium) extracts have rapidly replaced ephedra products, which were banned by the United States Food and Drug Administration (FDA) in April 2004 because of an association with serious adverse health effects.1-4 In addition to C. aurantium, new ephedra-free supplements frequently contain proprietary combinations of various botanical stimulants, and not uncommonly, the doses of these active constituents are not quantitated on the product label. The dried fruit peel of bitter orange, known in Chinese herbal medicine as Zhi shi, is a traditional remedy for gastrointestinal ailments.5 The known active components of Drs. Haller and Benowitz have served as paid expert witnesses in litigation involving manufacturers of dietary supplements. Requests for reprints should be addressed to Christine A. Haller, MD, University of California, San Francisco, Box 1220, San Francisco, CA 94143.

E-mail address: dchaller at 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2005.02.034

The American Journal of Medicine (2005) 118, 998-1003 C. aurantium include the adrenergic amines synephrine, octopamine, hordenine, tyramine, and N-methyltyramine. The predominant constituents are synephrine and octopamine, which are structurally similar to norepinephrine. The pharmaceutical forms of synephrine, phenylephrine and Neosynephrine, are commonly used to treat hypotension and nasal congestion. Synephrine and octopamine also occur endogenously. Although their physiologic roles have not been fully characterized, these substances appear to interact with trace amine receptors in the brain and may be involved in the pathogenesis of migraine headaches.6 Peripherally, synephrine acts at _1-adrenergic receptors, resulting in vasoconstriction and increased blood pressure.7 There is some evidence that synephrine and octopamine also have _3-adrenergic agonist activity, which could account for purported lipolytic actions, although this has not been demonstrated in humans.5

Methylxanthines such as caffeine, theophylline, and theobromine occur naturally in many plants. Extracts of Paullina cupana (guarana), yerba mate, cocoa, and green tea are frequently found in herbal weight-loss dietary supplements. In some products, the total caffeine per dose is equivalent to as much as three to four cups of coffee. Caffeine is a central nervous system (CNS) stimulant and increases systolic blood pressure through adenosine inhibition. 8 It is also known to enhance the effects of other sympathomimietics such as ephedrine and phenylpropanolamine. 9,10

Because newly re-formulated weight-loss supplements contain botanicals that possess sympathomimetic activity, there is concern that these products may pose some of the same health risks as ephedra.5 Few studies have been conducted on the efficacy or safety of ephedra-free dietary supplements, and little is known about the potential adverse effects of taking C. aurantium alone or in combination with other herbal ingredients. Although reports of adverse effects have not been conclusively linked with use of C. aurantium extracts, there is one published report of stroke in a 38-year-old man, 11 one case of exercise-induced syncope and QT prolongation in a 22-year-old woman, 12 and a possible case of myocardial infarction in a 55-year-old woman, 13 associated with use of dietary supplements containing bitter orange. Because existing surveillance systems for detecting adverse reactions to dietary supplements are not very effective, 14 other cases of toxicity related to C. aurantium may have occurred and been unrecognized or unreported.

We are aware of just one published study of the effects of a synephrine-caffeine herbal weight loss supplement in humans. 15 Although no adverse effects were reported and no increase in blood pressure was observed after six weeks of use, frequent hemodynamic monitoring was not performed. In a clinical study involving oral administration of freshly squeezed juice of C. aurantium to 12 normotensive adults, heart rate and blood pressure were not affected. 16 However, a rodent study showed that high doses of extracts of C. aurantium cause ventricular arrhythmias and death. 17 To date, there have been no human studies correlating acute hemodynamic effects with plasma synephrine levels after oral ingestion of weight loss products that contain C. aurantium extracts. In this report, we present novel data on the pharmacokinetics and cardiovascular effects of C. aurantium taken orally as two different dietary supplement formulations.


Clinical study

This was a randomized, double-blind, 3-arm crossover study involving 10 healthy adults aged 18 to 49 years. All volunteers gave written informed consent before study participation. The Committee on Human Research at the University of California, San Francisco (UCSF) approved the study protocol. Subject eligibility was determined by medical history, physical examination, and screening laboratory tests that included complete blood count, serum chemistry tests, urine toxicology testing for illicit drug use, and urine pregnancy testing for women. Exclusion criteria included any history of cardiac, thyroid, liver, or renal disease, hypertension, diabetes, psychiatric or seizure disorder, pregnancy or lactation, prescription or illicit drug use, cigarette smoking, and heavy use of caffeine (_3 cups of coffee or equivalent per day).

Subjects were instructed to abstain from caffeine, or any over-the-counter or herbal product for 24 hours before the study. Subjects were admitted to the General Clinical Research Center at San Francisco General Hospital on the night before testing and fasted after midnight. At 8 AM the next morning, subjects were given a single oral dose of placebo, Advantra Z (Nutratech, Inc., Wayne, NJ), or Xenadrine EFX (Cytodyne Technologies Inc., Manasquan, NJ). The product formulations and doses of active ingredients that were measured in the dietary supplements are shown in Table 1. The placebo and supplement doses were packaged in identical gelatin capsules for blinding of the research subjects, nurses, and clinical research staff. Treatment order was determined by use of an online randomization program. 18 Subjects rested in their hospital room after dosing. Caffeine-free meals were given beginning 3 hours after dosing. A minimum one-week washout period occurred between the 3 study visits.


Venous blood samples (7 mL) were collected from an indwelling forearm catheter at baseline, 30, 60, and 90 minutes, and 2, 3, 4, 6, 8, and 12 hours after dosing. The blood was centrifuged and the separated plasma was stored at -20C for subsequent analysis of synephrine, octopamine, and caffeine concentrations. Heart rate and blood pressure were recorded with an automatic sphygmomanometer for Haller et al Hemodynamic effects of ephedra-free weight-loss supplements in humans 999 one hour before dosing, and then before each blood draw. Questionnaires that rate physical symptoms, moods, and emotions were administered at baseline and 1, 2, and 6 hours after dosing. Subjects were instructed to rate on a 10-cm visual analog scale how they feel at the time, from zero (none) to 10 (strongest) for feeling lethargic, nauseated, shaky, heart pounding, sweating, flushed, headache, alert, able to concentrate, calm, upbeat, or irritable.


Plasma concentrations of synephrine, octopamine, and caffeine were measured over 12 hours, and pharmacokinetic parameters of maximum plasma concentration (Cmax), elimination half-life (t1/2), area under the plasma concentration time curve (AUC), total clearance (CL/F), and apparent volume of distribution (V/F) were estimated by non-compartmental methods with use of WinNonlin (Version 3.1, Pharsight Corporation, Mountain View, Calif). AUC was calculated using the log/linear trapezoidal rule for the 12- hour post-dosing period and extrapolated to infinity (0-_). The time to reach the maximum plasma concentration, Tmax, was estimated directly from the plasma concentration-time data. The dietary supplements were analyzed for caffeine by GC/MS, and for synephrine and octopamine content by high-performance liquid chromatography.14 A novel tandem LC/MS-MS method developed in our laboratory to measure ephedrine alkaloids19 was modified to measure levels of synephrine and octopamine in plasma samples.

This involved synthesis of a stable isotope-labeled internal standard (synephrine-d3) and development of an extraction procedure that is suitable for synephrine and octopamine. Briefly, the method involves precipitation of plasma proteins, addition of pH 10 buffer, and extraction with a mixture of methylene chloride, ethyl acetate, and isopropyl alcohol. The extract is evaporated, reconstituted in the HPLC mobile phase, and an aliquot is injected into the LC-MS/MS system. Atmospheric pressure chemical ionization (APCI) is used, the mass spectrometer is operated in the selected reaction-monitoring mode, and quantitation is achieved using the internal standard method, with standard curves generated using linear regression. Standard curves were linear from 1 to 100 ng/mL, and accuracy was excellent for blank plasma spiked with 5, 20, and 50 ng/mL.


All results are expressed as means _ standard deviations (SD) or medians _ 95% confidence intervals (CI) in the text and tables, and, for clarity, as means _ standard errors (SEM) in the figures. Pair-wise comparisons of changes from baseline were made between treatments at all times after dosing with paired t-tests, or Wilcoxon signed-ranks tests for nonparametric data. All of the data were analyzed using SAS (Version 8.2. SAS Institute, Cary, NC). Differences with a two-sided P _0.05 were considered statistically significant.


Five men and five women aged 19 to 42 years (mean 27 years) were enrolled and all subjects completed the study. No adverse events occurred. Subjects ranged in weight from 51.2 to 84.7 kg (mean 70.3 kg). The race/ethnicity of the subjects were white (4), African-American (2), Hispanic (2), and Asian/Pacific Islander (2). The mean plasma concentrations of synephrine over time after dosing with Xenadrine EFX and Advantra Z are shown

Figure 1 Plasma concentrations of synephrine over time after oral dosing with Xenadrine EFX (‘) and Advantra Z (_). Data are means _ standard errors.

Table 1 Quantities of active dietary supplement ingredients determined by laboratory analysis using HPLC and GC-MS Average amount per capsule or tablet (mg) Xenadrine EFX* Advantra Z Synephrine 2.75 15.6 Octopamine 2.96 trace Caffeine 119.6 – Study dose amount (mg) 2 capsules 3 tablets Synephrine 5.5 46.9 Octopamine 5.7 trace Caffeine 239.2 –

*Listed ingredients include: Vitamin C (100 mg), vitamin B6 (10 mg), pantothenic acid (12 mg), magnesium (10 mg), and a proprietary Thermodyne complex (1415 mg) consisting of Tyroplex (l-tyrosine, acetyl-l-tyrosine), green tea extract, Seropro (cocoa extract containing phenylethylamine, tyramine, and theobromine), yerba mate, d-methionine, ginger root, isotherm (3,3=,4=,5-7 pentahydroxyflavone, 3,3=,4=,7-tetrahydroxyflavone), bitter orange (synephrine, n-methyltyramine, hordenine, octopamine, tyramine), DMAE (2-dimethylaminoethanol), grape seed extract. Dose amounts are not provided on product label.

Listed ingredient: Citrus aurantium (10 mg synephrine per tablet). 1000 The American Journal of Medicine, Vol 118, No 9, September 2005 in Figure 1, and the pharmacokinetic parameters for synephrine are summarized in Table 2. After correcting for dose differences, there was no significant difference in synephrine pharmacokinetics between the multi-ingredient and single-ingredient dietary supplements. With ingestion of Xenadrine EFX, mean caffeine pharmacokinetics were Tmax 90 minutes; Cmax 5.1 _ 1.3 _g/mL; t1/2 7.8 _ 3.1 hours, AUC(0-_) 66.9 _ 36.1 _g.hour/mL; CL/F 75.5 _ 35.7 mL/min; V/F 42.7 _ 10.3 L. Pharmacokinetic parameters could not be estimated for octopamine because 99% of the plasma samples measured serially after dosing with Xenadrine EFX and Advantra Z were below the limit of quantitation of 0.2 ng/mL for octopamine. As shown in Figures 2 and 3, Xenadrine EFX significantly raised mean systolic and diastolic blood pressure compared with placebo, with maximal increases observed 2 hours after ingestion. Peak changes from baseline were 9.6 _ 6.2 mm Hg for systolic blood pressure (P _ 0.047 vs placebo), and 9.1 _ 7.8 mm Hg for diastolic blood pressure (P _ 0.002 vs placebo). Advantra Z did not raise systolic or diastolic blood pressure. Heart rate was significantly increased from baseline at 6 hours after dosing with both treatments (Figure 4), with mean values of 16.7 _ 12.4 beats per minute for Xenadrine EFX, (P _ 0.011 vs placebo); and 11.4 _ 10.8 beats per minute for Advantra (P _ 0.031 vs placebo).

Subjective responses to the study treatments were significant for a mean difference in alertness 2 hours after dosing with Xenadrine EFX compared with Advantra Z (P _ 0.006). The mean score for alertness of 3.5 with Xenadrine EFX versus 1.2 with placebo approached statistical significance (P _ 0.07). The mean alertness score for Advantra Z decreased from baseline to -0.55 at 2 hours. No other differences in subjective responses to the treatments were observed.


In this study, we present novel data on the disposition characteristics and effects of synephrine taken orally as C. aurantium. We demonstrate for the first time that some ephedra-free weight-loss dietary supplements raise blood pressure in healthy, normotensive adults. These findings indicate that re-formulated weight loss supplements have similar acute cardiovascular stimulant actions as banned ephedra products and could cause adverse health effects in some individuals. From the plasma concentration data, it appears that synephrine and octopamine are poorly absorbed or rapidly metabolized when taken orally, as the Cmax for both drugs was less than 1 ng/mL after dosing with Xenadrine EFX.

A Table 2 Summary of synephrine pharmacokinetics after oral dosing with C. aurantium Pharmacokinetic parameter Xenadrine EFX Advantra Z Tmax (minutes) 90 75 Cmax (ng/mL) 0.27 _ 0.14 2.85 _ 0.86 T (h) 3.0 _ 2.7 3.1 _ 2.2 AUC/dose (minng/mLmg) 15.4 _ 9.5 14.6 _ 6.0 V/F (L) 16347 _ 6987 19141 _ 10665 CL/F (L/min) 88.9 _ 51.8 80.3 _ 33.5 Values are means _ standard deviations, except for Tmax, for which medians are shown. Cmax _ maximum plasma concentration; Tmax _ time to maximum plasma concentration; T1/2 _ elimination half-life; AUC/dose _ area under the plasma concentration versus time curve extrapolated to infinity, divided by synephrine dose; V/F _ apparent volume of distribution divided by bioavailability; CL/F _ clearance divided by bioavailability. Figure 2 Change from baseline in systolic blood pressure over time after oral dosing with Xenadrine EFX (‘) and Advantra Z (_), and placebo (OE). Data are means _ standard errors. P _0.05 for (‘) vs (OE) at 2 hours and 4 hours. Haller et al Hemodynamic effects of ephedra-free weight-loss supplements in humans 1001 previous pharmacokinetic study of pharmaceutical synephrine (Sympatol) showed that the time to peak plasma concentration was 1 to 2 hours, and the elimination half-life was about 2 hours,20 which are consistent with our findings.

Our study suggests that C. aurantium, when ingested alone in modest doses, is unlikely to have significant pharmacological activity. The finding that ingestion of Advantra Z, containing an eightfold higher dose of synephrine than Xenadrine EFX, had no effect on blood pressure supports this hypothesis. However, when taken as a combination product with other active herbal ingredients including caffeine, significant increases in blood pressure resulted. In previous studies, caffeine has been shown to modestly increase systolic but not diastolic blood pressure. 10 That both systolic and diastolic blood pressure were increased with Xenadrine EFX suggests that the vasopressive effects are not due to caffeine alone but potentially related to the actions or interactions of other constituents in the multi-ingredient product. A transient but significant increase in heart rate was observed with both Xenadrine EFX and Advantra Z, suggesting that C. aurantium may have some _-1 adrenergic activity. A previous investigation that involved oral administration of 20 mg/kg C. aurantium extract to rats resulted in ventricular tachycardia and widening of the QRS interval; and in another study involving guinea pigs, synephrine had Figure 3 Change from baseline in diastolic blood pressure over time after oral dosing with Xenadrine EFX (‘) and Advantra Z (_), and placebo (OE). Data are means _ SEMs. P _0.05 for (‘) vs (OE) at 1 hour and 2 hours. Figure 4 Change from baseline in heart rate over time after oral dosing with Xenadrine EFX (‘) and Advantra Z (_), and placebo (OE). Data are means _ standard errors. P _0.05 for (‘) and (_), vs (OE) at 6 hours. 1002 The American Journal of Medicine, Vol 118, No 9, September 2005 positive chronotropic activity on atrial tissue.

These findings indicate that additional human studies of the effects of C. aurantium on cardiac electrophysiology are needed. The lack of significant subjective reports of mood and emotional responses to the treatments suggests that C. aurantium does not have pronounced psychoactive stimulant actions, which may indicate that synephrine has poor CNS penetration. Only Xenadrine EFX resulted in an increased score for alertness, which is likely attributable to the CNS stimulant effects of caffeine.10 Whether dietary supplements that contain C. aurantium result in increased lipolysis, accelerated metabolic rate, or decreased appetite was not the focus of this study. As with any drug, a risk-benefit analysis is needed to determine if any potential advantage for weight loss outweighs the possible adverse effects of the product. Chronic dosing studies are needed to determine if the acute hemodynamic effects seen with Xenadrine EFX persist or diminish with repeated use. Until such data are available, physicians should caution patients about the use of ephedra-free weight-loss dietary supplements and monitor blood pressure in those who choose to use these supplements. Individuals with hypertension, heart disease, or other pre-existing conditions that could be exacerbated by the sympathomimetic effects of botanical stimulants should avoid use of these products.


This work was funded by Public Health Service grants K23AT00069-04 (National Center for Complementary and Alternative Medicine), DA12393, and a General Clinical Research Center Award (M01RR00083-41). We are grateful to Minjing Duan for his analytical chemistry work, Gina Lowry and Mary Kay Pederson for subject recruitment and assistance with the clinical study, Faith Allen for oversight of protocol development and data management, Dr. Peter Bacchetti and Dr. Alan Bostrom for statistical analysis, and the nurses and staff of the UCSF General Clinical Research Center at San Francisco General Hospital for care of the research subjects. We also thank Dr. Bill Gurley for performing the analysis of the dietary supplements used in this study.


  1. US Food and Drug Administration. Questions and answers about FDA’s actions on dietary supplements containing ephedrine alkaloids. Available at: qa_020604.html. Accessed May 28, 2004.
  2. Shekelle PG, Hardy ML, Morton SC, et al. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance. JAMA. 2003;289:1537-1545.
  3. Samenuk D, Link MS, Homoud MK, et al. Adverse cardiovascular events temporally associated with ma huang, an herbal source of ephedrine. Mayo Clin Proc. 2002;77:12-16.
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  5. 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.
  6. D’Andrea G, Terrazzino S, Fortin D, Cocco P, Balbi T, Leon A. Elusive amines and primary headaches: historical background and prospectives. Neurol Sci. 2003;24(suppl 2):S65-S67.
  7. Brown CM, McGrath JC, Midgley JM, et al. Activities of octopamine and synephrine stereoisomers on _-adrenoceptors. Br J Pharmacol. 1988;93:417-429.
  8. Benowitz NL. Clinical pharamcology of caffeine. Ann Rev Med. 1990; 41:277-288.
  9. Brown NJ, Ryder D, Branch RA. A pharmacodynamic interaction between caffeine and phenylpropanolamine. Clin Pharmacol Ther. 1991;50:363-371.
  10. Haller CA, Jacob P, Benowitz NL. Enhanced stimulant and metabolic effects of ephedrine and caffeine. Clin Pharmacol Ther. 2004;75:259- 273.
  11. Bouchard NC, Greller HA, Hoffman RS, Nelson LS. Ischemic stroke from “ephedra-free” dietary supplement containing synephrine (abstract). J Toxicol Clin Toxicol. 2004;42:137.
  12. Nasir JM, Durning SJ, Ferguson M, Barold HS, Haigney MC. Exercise- induced syncope associated with QT prolongation and ephedrafree Xenadrine. Mayo Clinic Proc. 2004;79:1059 -1062.
  13. Nykamp DL, Fackih MN, Compton AL. Possible association of acute lateral-wall myocardial infarction and bitter orange supplement. Ann Pharmacother. 2004;38:812- 816.
  14. Adverse Event Reporting for Dietary Supplements: An Inadequate Safety Valve. OEI-01-00-00180 ed: Washington, DC: Office of the Inspector General, HHS; 2001.
  15. 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 TherRes. 1999;60:145-153.
  16. 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;41:1059-1063.
  17. Calapai G, Firenzuoli F, Saitta A, Squadrito F, et al. Antiobesity and cardiovascular toxic effects of Citrus aurantium extracts in the rat: a preliminary report. Fitoterapia. 1999;70:586-592.
  18. Accessed June 2, 2004.
  19. Jacob P, Haller CA, Duan M, Yu L, Peng M, Benowitz NL. Determination of ephedra alkaloids and caffeine levels in dietary supplements and biological fluids. J Anal Toxicol. 2004;28:152-159.
  20. Hengstmann JH, Aulepp H. Pharmacokinetics and metabolism of 3Hsynephrine. Arzneimittelforschung. 1978;28(12):2326 -2331. Haller et al Hemodynamic effects of ephedra-free weight-loss supplements in humans 1003

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Citrus Aurantium Effect


Thermogenic effect of beta-sympathicomimetic compounds extracted from citrus aurantium in humans.

Philip Hedrei, Dr. Réjeanne Gougeon; McGill Nutrition and Food Science Center H6.9, Royal Victoria Hospital.


The development of obesity is postulated to occur as an interaction between familiar and environmental factors. The genetically predetermined abnormalities include a low rate of fat oxidation, which itself may lead to an energy imbalance, and a lower resting energy expenditure(REE) in conjunction with diets high in fat content (1,2,3). Energy expenditure can be thought of as encompassing three components:
1) resting metabolic rate (RMR), defined as the energy requirements for maintaining normal bodily functions at rest,
2) thermic effect of exercise,referring to the increase in energy production of the body in response to physical activity,manifested as heat, and
3) thermic effect of food (TEF), or the increase in energy production post-prandially (4).

The TEF is associated with the energy requirements for processing a meal, namely increased activity of ATP-dependent ion channels, active absorption of nutrients, increased protein turnover and increased substrate cycling. Though the TEF may represent a small portion of the total energy expenditure, some studies have demonstrated defective thermogenesis in experimental rodent models of obesity,while others show reduced thermic response to food in obese human subjects (5,6,7). Hence, TEF could play a role in the development of or maintenance of obesity. More specifically, a blunted thermic response to a meal has been shown to imply a significant energy imbalance in obese individuals (4).

The sympathetic nervous system (SNS), implicated in the regulation of the mobilization of energy reserves, may also be subject to defects thereby predisposing to weight gain (8). Beta adrenergic receptors are involved in the pathways of lipolysis, glycogenolysis and thermogenesis, with lipolysis and thermogenesis being mediated via the ß3 receptor (9,10). It has been observed that genetically obese rats exhibit low sympathetic outflow and/or responsiveness in various tissues. In such animal models, symathicomimetic agents could effectively normalize body weight due to stimulation of thermogenesis in brown adipose tissue via the ß3-adrenoceptor pathway(9).

Studies with the ß3-adrenoceptor also show a high degree of selectivity for thermogenesis, supporting its potential as an anti-obesity agent (11,12). Hence, the SNS and ß3-adrenoceptor represent another target for intervention in obesity. Indirect-acting sympathicomimetic compounds potentiate the release of epinephrine and norepinephrine at pre-synaptic sites in the SNS. By acting at ß3 receptors, these catecholamines accelerate the removal of unwanted fat stores by increasing the rate at which fat is released from body stores (lipolysis), while simultaneously increasing the metabolic rate (thermogenesis) (13). Drugs such as Ephedrine, a ß-sympathicomimetic, have consistently demonstrated an increase in thermogenesis and improved weight loss in numerous studies (14,15,16,17). Because such drugs simultaneously activate ß1 and ß2 receptors, adverse side effects such as tachycardia, insomnia and tremors are often reported. Interestingly, studies by Dulloo in 1993 suggest that with chronic administration, ephedrine down-regulates adrenoceptor subtypes associated with unwanted cardiac or pressor effects, thereby generating its own selectivity for desirable anti-obesity effects.

Zhi-Thin™ is an extract of Citrus Aurantium containing a family of indirect-acting ß-sympathicomimetics that stimulate metabolic processes, increase lipolysis and can exert mild hunger-suppressant effects (13). These active adrenergic agents include synephrine, hordenine, octopamine, tyramine and N-methyltyramine, whose structures are illustrated below:

Synephrine has been shown in preliminary studies to be a little more than half as potent as ephedrine, and has reduced central nervous system stimulation. Preliminary non-controlled studies have confirmed that this compound is well tolerated and appeared to enhance weight loss(13). Hence, the thermogenic potential of Citrus Aurantium and other indirect-acting thermogenic substances may be useful in the treatment of obesity, given that obese individuals appear to exhibit reduced SNS activity and a reduced thermic response to food. The purpose of this study was to assess the acute thermogenic response of Citrus Aurantium at rest in lean and obese individuals. We sought to determine the thermic effect of the alkaloid mixture when consumed orally with water and when consumed with a mixed meal. We also wanted to assess whether the metabolic rate of lean and obese diabetic and non-diabetic individuals would differ in response to the consumption of the alkaloid compound. Our starting hypotheses were as follows:

  1. Alkaloids extracted from Citrus Aurantium, particularly Synephrine, induce a notable increase in metabolic rate, when taken orally in a capsule form with water.
  2. Citrus Aurantium potentiates the thermic effect of a mixed meal in lean and obese diabetic and non-diabetic subjects during rest.
  3. As a result of its sympathicomimetic ability, Citrus Aurantium will cause an increase in serum and urinary concentrations of catecholamines.

Materials and Methods

Seven healthy lean subjects (6 males, 1 female) were recruited to participate in our metabolic study at the McGill Nutrition Centre. All subjects chosen were non-smokers and weren’t taking any drugs. Their suitability for participation in the study was assessed by an M.D. in a thorough medical exam, and blood tests for HepB Ag and HIV were performed. Persons with hepatic, cardiovascular, renal or pulmonary dysfunction, gout, or claustrophobia were excluded. Subjects were then informed as to the study protocol, the implications of their participation, as well as potential risks. It was made clear that the process of indirect calorimetry presented no health risk whatsoever, that there was the potential for bruising where the catheter was concerned, and that the total volume of blood drawn represented less than a blood donation. Each of them signed a consent form approved by the RVH Department of Medicine, Human Ethics Committee. The study comprised three day- long sessions at the McGill Nutrition and Food Science Center. All participants were asked to refrain from eating and drinking, except water, after 8:00 pm the evening before each session. Subjects thus arrived fasted at the McGill Nutrition Center between 7:30 and 8:30 am, and were told to rest in bed for half an hour before the commencement of each experiment. Following this, indirect calorimetry was used to record a 20-minute baseline resting metabolic rate (RMR). The average of the last 15 minutes was used to calculate the 24 hour resting energy expenditure (REE) according to the de Weir equation (19).

Indirect calorimetry was used to determine O2 consumption and CO2 production, using the Deltatrac metabolic monitor ventilated hood (Sensormedics, Anaheim, CA). This machine consists of a transparent plastic hood, which is placed over the head while the subject is lying down. A plastic tarp connected to the canopy drapes over the subject’s neck and shoulders, and renders the hood airtight when tucked underneath the pillow. A slight negative pressure and a gaseous and temperature steady state are maintained within the canopy throughout the study. Calibrated analyzers in the machine measure minute by minute averages of O2 and CO2 concentrations, using air fed by a gas sampling tube directly connected to the upper part of the hood. From this, minute by minute VCO2 and VO2, R.Q. (VCO2/VO2) and energy expenditure are recorded on a printout from the machine, and are expressed as extrapolated values for 24 hours.

The set of conditions following the 20-minute RMR differed between each of the three sessions, and the order of the three sessions was randomized for each subject. On a given day, subjects had their metabolic rates monitored under one of the following three conditions:
1) after consumption of a 392 Calorie mixed meal, over a period of 336 minutes,
2) after consumption of 5 CitrusAurantium capsules over a period of 300 minutes, or
3) after consumption of both the 392 Calmixed meal and the 5 Citrus Aurantium capsules, over a period of 336 minutes. During the three sessions, the Deltatrac metabolic monitor was used continuously for periods of 40 minutes, with a 20 minute break per hour.

The mixed meal was presented in the form of two chocolate flavored food bars (Power 8R, Bariatrix International, Lachine, Quebec), each containing 196 calories of energy. Themacro nutrient content of the 392 Cal meal, as a percentage of total energy content, is 53% carbohydrate, 29% protein and 18% fat. Metabolic rates were measured for a period of roughly 6hours so as to obtain 60-70% of the TEF, thereby allowing for comparison of TEF between subjects (4).

Fat-free mass and percentage body fat was measured in each participant by the bio electrical impedance analysis method, using a 4-terminal bio impedance analyzer (BIA-103, RJL Systems,Detroit, MI). The procedure and anatomical sites for placement of electrodes was as specified by Lukaski and others. (20). Further anthropometric measures taken included weight (kg), height (cm) and body circumferences (cm). These measurements were taken before the start of the first session only, when subjects were in the fasted state.

Urine was collected during each of the sessions for analysis of urea and catecholamine, (E, NEand DOPA). Prior to measurement of the 20-minute baseline RMR, a “pre-study” urine sample was obtained, against which we compared urinary urea and catecholamines measured in urine collected during the actual TEF measurement. Aliquots of 10ml from each collection were acidified with HC1 to a pH of 3, and stored at -70°C until HPLC was used to determine dopamine, norepinephrine and epinephrine concentrations. An additional 4ml aliquot from each sample was used to obtain the urea concentration by the urease-Berthelot method (21). Allcatecholamine and urea concentrations were adjusted with respect to the volume of urine produced in each sample, and the time of each sample was noted.

A catheter was inserted into an anticubital vein and kept patent with isotonic saline for blood sampling. Ten cc of venous blood was sampled prior to consumption of the test meal (t=0) and then at 30, 60, 90, 120, 180, 240, 300 and 336 minutes. No blood sampling was done during the session in which the Citrus Aurantium capsules were consumed on their own.

Of the 10cc sampled at each tame period, 3cc was placed an a test tube containing trasylol, to be later centrifuged so that serum insulin could be assessed by radio-immunoassay (RIA) using I-125 (No. KTSP-11001). The remaining 7cc of blood was placed into a “green-top” vacuum sealed test tube containing heparin. After centrifugation, 1cc of plasma was extracted into a test tube for measurement of serum glucose concentrations using the Beckman glucose analyzer and the Beckman glucose reagent kit (No. 671640). The rest of the plasma was put into a test tube containing roughly 10mg sodium meta-bisulphite, for subsequent determination of serum catecholamine concentrations using HPLC. At the time of this writing, all of the serum samples are being stored at -20°C, awaiting testing.

Pulse rates and blood pressures were taken at the beginning of each session and during every break of the TEF measurement. Blood pressure was measured by a Pressurometer auscultatory automated blood pressure system.


In our 7 lean subjects, the 20 minute baseline RMR was found to be reproducible with high reliability between the three days of the test. Also, on any given day of the study, the hourly pulse and blood pressure recordings remained fairly constant with respect to the pre-TEF value taken just after the RMR, indicative of a state of relaxation.

Figure 1 compares the change in respiratory quotient (VCO2/VO2) between each of the three conditions, throughout the duration of the study. Each point on the graph represents the average R.Q. for all subjects at a particular point in time. Citrus Aurantium seemed to elicit an increase in R.Q. within the first 50 minutes of the study, both when consumed alone and in conjunction with the mixed meal bars.

Figure 2 compares the thermogenic effect, or increment above resting metabolic rate, of the three conditions. The “meal only” curve represents a typical thermogenic response to a meal, showing a peak metabolic rate within one and a half hours of consumption of the meal, after which the metabolic rate slowly returns to baseline. Of interest here is the increase in magnitude of the TEF peak from 0.88±0.11 KJ/min. to 1.08±0.09 KJ/min. with consumption of the meal and Citrus Aurantium. Also, our results show an increase in energy expenditure with the Citrus Aurantium capsules alone, with a peak of 0.56±0.16 KJ/min (p=0.024).

There was a 14.9±1.0% increase above resting energy expenditure when the capsules were added to the mixed meal, as compared to a 13.5±1.2% increase above REE with the mixed meal alone. The thermogenic effect of the meal and capsule combination was also greater when expressed as a percent increase above REE and as a percent of the ingested calories (converted to KJ), as illustrated in Figure 4.

Urinary epinephrine increased from 2.25±0.63 nmol/hr to 4.54±0.81 nmol/hour, and dopamine from 50.18±1.68 nmol/hr to 75.39±3.17 nmol/hr (p,0.05) after consumption of Citrus Aurantium alkaloid mixture (figure 3). Excretion of norepinephrine showed an insignificant decrease.


A minimum of 14 lean, 14 obese subjects with diabetes and 14 obese non-diabetic subjects are required in order to provide an 80% probability of detecting a difference of 8 Calories in metabolic rate with an intra-individual standard deviation of 6.4 Calories. More studies have to be performed in order to bring the sample size to an acceptable number.

Despite this, our preliminary results show trends which support some of our hypothesis with statistical significance. First of all, the significant increase in urinary epinephrine and dopamine excretion are indicative of the sympathicomimetic potential of Citrus Aurantium, for this implies an increased release of these catecholamines into the circulation from presynaptic sites. Our findings suggest that Citrus Aurantium potentiates the TEF of a mixed meal, as evidenced by an increased thermogenic response in lean subjects after consumption of the mixed meal and Citrus Aurantium combination. In addition, results so far indicate a measurable increase in metabolic rate upon consumption of Citrus Aurantium with water. These early results support the thermogenic potential of Citrus Aurantium. Furthermore, as no irregular changes in pulse pressure or blood pressure were reported, our results indicate that the alkaloid mixture is well tolerated,and provokes no tachycardia.

It is important to note that obese and obese diabetic subjects have not yet been challenged to the study, however we predict that there might be important differences in responsiveness to Citrus Aurantium in these individuals. The crucial affirmation of the clinical usefulness of this alkaloid mixture will come should the results be the same or greater in these individuals, as we predict.


I would like to thank the hard workers of the McGill Nutrition Center for their assistance in this research, especially Tina Venuta, Marie Lamarche, Mary Shingler and Dr. Jose Morais.References


  1. Astrup, A. The sympathetic nervous system as a target for intervention in obesity. Int J Obes1995;7:S24-S28.
  2. Bouchard, C., A. Tremblay, A. Nadeau, J.P. Despres, G. Theriault, M.R. Boulay, G. Lortie, C.Leblanc, and G. Fournier. Genetic effect in resting and exercise metabolic rates. Metabolism1989;38:364-370.
  3. Ravussin, E., S. Lillioja, W.C. Knowler, L. Christin, D. Freymond, W.G.H. Abbott, V. Boyce,APPENDIX J to ZHA-3DE7 B.V. Howard, and C. Bogardus. Reduced rate of energy expenditure as a risk factor for body weight gain. N Engl J Med 1988;318:467-472.
  4. Reed, G.W. and J.O. Hill. Measuring the thermic effect of food. Am J Clin Nutr 1996;63:164-169.
  5. Schultz, Y., T. Bessard, and E. Jequier. Diet-induced thermogenesis measured over a whole day in obese and non-obese women. Am J Clin Nutr .1984;40:542-552.
  6. Bessard, T., Y. Schultz, and E. Jequier. Energy expenditure and postprandial thermogenesis in obese women before and after weight loss. Am J Clin Nutr 1983;38:680-693.
  7. Swaminathan, R., R.F.G.J. King, J. Holmfield, R.A. Siwek, M. Baker, and J.K. Wales.Thermic effect of feeding carbohydrate, fat protein and mixed meal in lean and obese subjects.Am J Clin Nutr 1985;42:177-181.
  8. Spraul, M., E. Ravussin, A.M. Fontvieille, R. Rising, D.E. Larson, and E.A. Anderson.Reduced sympathetic nervous activity — a potential mechanism predisposing to body weightgain. J Clin Invest 1993;92:1730-1735.
  9. Walston, J., K. Silver, C. Bogardus, W.C. Knowler, F.S. Celi, S. Austin, B. Manning, A.D.Strosberg, M.P. Stern, N. Raben, J.D. Sorkin, J. Roth, and A.R. Schuldiner. Time of onset ofNIDDM and genetic variation in the ß3-adrenergic receptor gene. N Engl J Med 1995;333:343-347.
  10. Hoffstedt, J., H. Wahrenberg, A. Thorne, and F. Lonnqvist. The metabolic syndrome is related to ß3-adrenoceptor sensitivity in visceral adipose tissue. Diabetologia 1996;39:838-844.
  11. Connacher, A.A., W.M. Bennet, and R.T. Jung. Clinical studies with the ß3-adrenoceptoragonist BRL 26830A. Am J Clin Nutr 1992;55:258S-261S.
  12. Connacher, A.A., R.T. Jung, and P.E.G. Mitchell. Weight loss in obese subjects on a restricted diet given BRL 26830A, a new atypical ß3-adrenoceptor agonist. Br Med J1988;296:1217-1220.
  13. Jones, D., 1996 (unpublished data).14. Horton, T.J., and C.A. Geissler. Post-prandial thermogenesis with ephedrine, caffeine and aspirin in lean, pre-disposed obese and obese women. Int J Obes 1996;20:91-97.
  14. Tourbo, S., A. Astrup, L. Breum and F. Quaade. The acute and chronic effects ofephedrine/caffeine mixtures on energy expenditure and glucose metabolism in humans. Int JObes 1993;17:S73-S77.APPENDIX J to ZHA-3DE7
  15. Astrup, A., L. Breum, and S. Toubro. Pharmacological and clinical studies of ephedrine and other thermogenic agonists. Obes Res 1995;3(Suppl 4):537S-540S.
  16. Jequier, E., R. Munger, and J.P. Felber. Thermogenic effects of various ß3-adrenoceptoragonists in humans: their potential usefulness in the treatment of obesity. Am J Clin Nutr1992;55:249S-251S.
  17. Dulloo, A.G. Ephedrine, xanthines and prostaglandin inhibitors: actions and interactions in the stimulation of thermogenesis. Int J Obes 1993;17:S35-S40.
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  19. Lukaski, H.C., W.W. Bolonchuk, C.B. Hall, and W.A. Siders. J Appl Physiol 1986;60:1327-1332.
  20. Fawcett, J.K. and J.E. Scott. J Clin Path 1960;13:156-159.

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Citrus Aurantium and Obesity


Thermic Effect of Citrus Aurantium in Obese Subjects

Bhuvan Pathak, Dr. Réjeanne Gougeon; McGill Nutrition Center, Royal Victoria Hospital, Montreal


The chronic problem of obesity, though influenced by many environmental factors, is partly the result of genetic abnormalities leading to a reduced energy expenditure (EE). This lowered EE could result in a positive energy balance and therefore weight gain. EE in all individuals can be divided into three categories: (A) resting metabolic rate (RMR), (B) post-prandial thermogenesis or the thermic effect of food(TEF), and (C) the thermic effect of exercise. One factor which contributes to a lower EEis a low RMR, and another is a low TEF. TEF is defined as the acute increase in energy expenditure above the RMR after energy intake (1,2). Although TEF represents a relatively small fraction of total energy expenditure in lean individuals (10% of EE) (3),this value has been reported in some studies to be significantly lower in obese individuals(1,4,5).

It has also been shown that thermogenesis remains at lowered levels even in post-obese subjects compared with weight-matched controls, thus proving that lowered TEF might be a significant factor in the pathogenesis of obesity (4,6).One abnormality which causes this lower TEF is found in the T3 hormone derived from the thyroid which increases the proton permeability of the inner mitochondrial membrane and therefore leads to a decrease in the efficiency of energy production (7). A second and very important defect may be found in the sympathetic nervous system (SNS); more specifically decreased SNS activity and/or responsiveness of various tissues to SNS activity. The decreased responsiveness to SNS activity is concentrated at the ß-adrenoreceptors which mediate (among other things) lipolysis, thermogenesis, and glycogenolysis, and especially at the ß-3 receptors which mediate lipolysis and thermogenesis (8,9).

Since obese individuals seem to exhibit reduced SNS activity and thus a reduced TEF, an increase in energy expenditure (EE) through the mediation of thermogenesis may create a negative energy balance. This negative balance would favor weight loss and would be of clinical significance as an adjunct in the treatment of obesity, or could help prevent further weight gain.

Although ß-adrenergic drugs may successfully increase the rate of thermogenesis, many undesirable effects may also be obtained due to the coupled stimulation of other ß-adrenoreceptors. For example; ephedrine, a sympathomimetic alkaloid, enhances the thermogenic effect in an individual over time but at the same time presents negative effects on heart rate and blood pressure and thus cannot be used in patients suffering from hypertension (10). Other substances, however, have proved to increase the TEF while maintaining relaxed heart-rate levels. One such substance is a mixture of ephedra (containing both ephedrine and pseudoephedrine and known as MaHuang in Chinese medical literature) and caffeine which achieved the above-mentioned results in lean, obese, and obese-diabetic persons (10).

Citrus Aurantium (C.A.) has also already been tested in lean individuals and has shown encouraging results; the TEF of a mixed meal (in the form of two food bars) was enhanced when taken with C.A. in a pill form (11). The pills taken alone also caused a small but significant increase in EE. C.A. caused increased respiratory quotient (VCO2/VO2) values within the first fifty minutes of the study when consumed alone as well as conjointly with a mixed meal. Finally, urinary catecholamines including dopamine and epinephrine increased when the C.A. was consumed, while norepinephrine excretion did not change significantly.

The purpose of this study is to evaluate whether alkaloids extracted from the immature fruit of C.A. induce a significant increase in the metabolic rate when taken orally in the capsule form with water, and potentiate the thermic effect of a mixed meal in(otherwise healthy) obese subjects during rest. The extract of C.A. (labeled as Zhi-Thin) contains small amounts of synephrine and octopamine which are direct and indirect acting adrenergic agents with ß-agonist activity thus potentially increasing lipolysis and fat oxidation (12).

The original hypotheses for this study remain consistent with those of the C.A. study done in lean subjects:
1.Alkaloids extracted from Citrus Aurantium, particularly synephrine, induce a notable increase in the metabolic rate, when taken orally in a capsule form with water.
2.Citrus Aurantium potentiates the thermic effect of a mixed meal in lean and obese diabetic and non-diabetic subjects during rest.
3. As a result of its sympathomimetic ability, Citrus Aurantium will cause an increase in serum and urinary concentrations of catecholamines.(11)

Materials and Methods

Subjects: The majority of the subjects recruited for this study were selected from a pool of subjects previously involved in an eight-week study concerning the effect of a reduced calorie diet in conjunction with C.A. or placebo on weight loss. Their clinical characteristics are shown in Table 1. Five women were recruited; they underwent a thorough medical examination to assess whether they were appropriate candidates for the study. This meant that the obese subjects had to be devoid of health problems such as diabetes, high blood pressure, liver and renal disease, etc…. The subjects also had their heart rate and blood pressure taken, and were screened for HIV and Hepatitis B viruses to ensure the safety of those involved in the study.

Finally, the subjects were made aware of the minimal risks associated with participation in the study such as bruising with the insertion of the catheter (required for the withdrawal of a total volume of blood that equaled less than that of a blood donation) and possible allergic reactions to the food bar used as a controlled mixed meal. The subjects were also told not to expect any weight loss since the study was measuring the acute effect of C.A. over a few hours rather than the prolonged effect over a few weeks or months. The women were then required to sign a consent form approved by the Royal Victoria Hospital’s Department of Medicine

Human Ethics Committee prior to the start of the study. The subjects were non-smokers at the time of the study, and had other similar habits (occasional alcohol and moderate coffee drinking for example). Characteristic Value Age (yrs) 49.4 ± 4.6BMI (kg/m) 34 ± 5.8 Waist-Hip Ratio 0.81 ± 0.07Arm Circumference (cm) 35.1 ± 4.1Weight (kg) 79.8 ± 14.5Fasting np R.Q. 0.81 ± 0.02%Body Fat 43.2 ± 9.2RMR (kilocalories) 1247 ± 114

Anthropometric Measurements: The subjects had their height and weight measured, and their percent body fat was determined using bioelectrical impedance analysis (BIA) (13,14) followed by calculations using the Lukaski equation (15). BIA is a painless, non-invasive procedure which sends electrical impulses through the body via electrodes. BIA measures the different values of resistance to electrical current caused by different body concentrations of materials such as fat and water. Resistance from BIA readings were taken using two different instruments, namely the BIA-103 (RJL systems, Detroit, MI) and the Tanita Body fat Analyzer (model TBF-105) to ensure accuracy and consistency in the readings.Finally, body circumferences including hip, waist, and upper arm were taken.

The Thermic Effect: On all three mornings of the study the subjects arrived at the Nutrition Center in the fasted state, and were asked to rest in a chair or bed for approximately half an hour to allow their metabolic rate to return to its resting level. The resting metabolic rate (RMR)was then measured for twenty minutes with an indirect calorimeter, Deltatrac Metabolic Monitor (Sensor Medics, Anaheim, CA). Indirect calorimetry involves the placement of a transparent, plastic canopy over the head and shoulders of the individual. The subject,in the supine position, must not make any sudden movements and must breathe normally while the calorimeter measures the minute by minute O2 and CO2 changes used to calculate the respiratory quotient (R.Q.) and RMR/24hrs (16). An average of the last fifteen minutes is taken as a value for the subject’s RMR. Heart rate and blood pressure were then taken, after which the subjects were asked to eliminate and discard any urine prior to the intake of foods and/or C.A.There were three different protocols which then followed (one for each of the three visits) and they were performed in random order for each subject. The studies were named as follows:

•Thermic Effect of Food #1 (TEF 1): the effect of a mixed meal only
•TEF 2: the effect of C.A. only
•TEF 3: the effect of the mixed meal in conjunction with C.A.The mixed meal was administered in the form of two PWER8EXP BAR POWERTHERM food bars. PWER8EXP contained a total of 209 (874 kJ)calories with 29%derived from proteins (15.3g), 48% from carbohydrates (27.3g), and 22% from fats (5.0g) (17).

Treatment: The subjects were given the appropriate products to consume (according to the study being done) and were placed under the ventilated hood for 40 minutes. At the end of the 40 minutes, they were given a 20 minute break during which they were asked to refrain from moving too much, and during which their heart rate and blood pressure were measured. This cycle was repeated until the effect of the consumed products wore off causing the RMR to return more or less to its baseline value (usually six cycles for TEF 1and 3, and four cycles for TEF 2).

Analytical Methods: Furthermore, all pre-study (overnight) urines as well as study urines were collected and preserved using 6M HCl added to a pH of 2-3. Aliquots were then stored at-20°C and -70°C to be tested for urea and catecholamines (epinephrine, norepinephrine,and dopamine) later on.

Also, for TEF 1 and 3, 10 ml samples of blood were taken from the subject att=0′, 30′, 60′, 90′, 120′, 180′, 240′, 300′, and 360′. Seven of the 10 ml were placed in green-capped heparin vacuum tubes to test for catecholamines and plasma glucose, while the other three ml were transferred to tubes containing trasylol to measure insulin. The aliquots to be tested for catecholamines were stored at -70°C (while those to be tested for glucose and insulin were stored at -20°C). The Beckman Glucose Analyzer (No. 671640)(18) was used to read plasma glucose levels. The subjects were given a regular hospital meal at the end of each of the three studies.

Statistical Analysis: The data were analyzed by calculating the surface area under the curve of the RMR graph and subtracting it from the area under the TEF curve. This value represented the effect of the given treatment and was used to calculate the percent increment above RMR.

Paired t-tests were then done to determine the significance of the values obtained for the percent increments and percent of the meal consumed. Finally, unpaired t-tests were done to validate comparisons between pre and post study catecholamines.


Figure #1 describes the TEF or the increase in energy expenditure above the baseline RMR. Each line represents one of the three different studies, as well as the means and standard error of the mean of five subjects. Each point represents the average measured EE every eight minutes of the protocol. The effect of food intake alone (TEF 1)on RMR reaches a peak at 30 minutes and then begins to decline gradually to baseline value, but never reaches it within the allotted time of the study (6 hours). This was also shown in studies done by Reed and Hill (1). On the other hand the increment effect of the meal given with C.A. (TEF 3) also reached a peak at 30 minutes but then energy expenditure continued to increase to an even greater value fully reached at roughly 72 minutes to taper off, not reaching baseline within the 6 hours of study. Finally, the intake of C.A. alone (TEF 2) was associated with an increase in EE above RMR that peaked at 30 minutes and gradually returned to baseline within 4 hours.

The thermic effect of the meals expressed as percent increment above RMR is shown in Figure #2. We found that the thermic response of the meal was significantly greater with the concurrent intake of Citrus Aurantium (18.3% meal plus C.A. compared with 13.8% meal alone, p=0.03) which represented a significantly greater contribution of the energy content of the meal (12.7% with C.A. compared with 9.6%, p=0.027). Figure #3 compares the increase in (R.Q.) in all three studies. Data are plotted as mean and standard error of the mean of every eight minutes. The response reflects that of the TEF with meal only (TEF 1); the R.Q. increased from 0.80 to 0.89 in roughly 30 minutes and then returned to the baseline value within 6 hours. With meal and C.A.(TEF 3) R.Q. increased significantly to a higher value of 0.91 within 88 minutes and then returned to baseline within 6 hours. C.A. (TEF 2) was associated with a slight increase from 0.81 to 0.83 within 30 minutes and then a return to the resting levels.

Finally, Figure #4 shows urinary excretions of epinephrine, norepinephrine, and dopamine in nmol/hr for and before the study with C.A. alone (TEF 2). Only epinephrine excretion increased significantly (p=0.012) from 0.352 nmol/hr without C.A. to 0.787 nmol/hr with the alkaloid. Excretions of norepinephrine and dopamine did not change significantly. It is also important to note that the heart rates and blood pressures of all the subjects remained constant throughout the entire study at levels equal to those taken at baseline.


The results of this study indicate that C.A. exhibits sympathomimetic behavior in obese subjects. Indeed, intake of the alkaloid substance was associated with greater thermic response to a mixed meal. Furthermore, C.A. when taken alone caused a measurable increase in RMR within 30 minutes thus indicating that the compound causes an increase in energy expenditure above baseline. The slight increase in R.Q. was a typical of the proposed situation since R.Q. values would decrease with increased lipolysis.

Secondly, the increased urinary excretions of epinephrine were indicative of the stimulatory effect of C.A. The compound acted in a sympathomimetic fashion thus increasing the mobilization of epinephrine. Finally, since the heart rates and blood pressures of all the subjects remained stable, C.A., at such doses, does not appear to be associated with unfavorable effects especially for individuals with hypertension.

Therefore, C.A. may selectively activate certain ß-adrenergic receptors in charge of lipolysis and thermogenesis.The studies done with C.A. to date have involved healthy lean and obese subjects. In both populations, the thermic effect of a mixed meal expressed as a percent increment above RMR was significantly increased when taken with C.A. (p=0.040), despite the small number of subjects studied. More obese non-diabetic subjects need to be studied if they are to be compared to the lean population, as well as to affirm whether the R.Q. values actually increase or decrease (the studies are ongoing at the present time).Furthermore, the effect of C.A. will be studied in obese type 2 diabetic persons in order to further evaluate the effectiveness of this compound in that population.

It is conceivable that the effect may be detectable or amplified in individuals characterized by central abdominal obesity. Although the increment in heat production was significantly greater in our subjects when given citrus aurantium, the increase in energy expenditure represented an average of 12 kcalories i.e.. 12.7 compared with 9.6 %of 418 kcalories, the energy content of the meal, or 53.1 compared with 40.1 kcalories. The effect was obtained early after intake of C.A at the maximum dose recommended, as shown in lean subjects in whom the response appears to be of a lower magnitude. This study shows that C.A. may increase the thermic response of a high protein meal by 4%, a value that could represent 60 kcalories per day. The latter as well as the clinical benefit for successful weight control of such increment remain to be demonstrated.


I would like to thank the team at the McGill Nutrition Center, especially Dr. RéjeanneGougeon, Marie Lamarche, and Mary Shingler for their time spent teaching, helping and guiding me along this study.


  1. Reed GW., 0 Hill J. Measuring the thermic effect of food. Am J Clin Nutr1996;63;164-9.
  2. Katzeff HL, Danforth E Jr. Decreased thermic effect of a mixed meal during over nutrition in human obesity. Am J Clin Nutr 1989;50;915-21.
  3. D’Alessio DA, Kavle EC, Mozzoli MA, et al. Thermic effect of food in lean and obesemen. J Clin Invest 1988;81;1781-89.
  4. Weststrate JA. Resting metabolic rate and diet-induced thermogenesis: a methodological reappraisal. Am J Clin Nutr 1993;58;592-601.
  5. Gougeon R. Thermic and metabolic responses to oral glucose in obese subjects withnon- insulin-dependent diabetes- mellitus treated with insulin or a very-low-energy diet.Am J Clin Nutr 1996;64;78-86.
  6. Schutz Yves, Golay A, Felber J-P, Jequier E. Decreased glucose-induced thermogenesis after weight loss in obese subjects: a pre disposing factor for relapse of obesity? Am J Clin Nutr 1984;39;380-7.
  7. Freake HC, Oppenheimer JH. Thermogenesis and thyroid function. Rev Nutr1995;15;263-91.
  8. Walston J, Silver K, Bogardus C, Knowler WC, Celi FS, Austin S, Manning B,Strosberg AD, Stem MP, Raben N, Sorkin JD, Roth J, Schuldiner AR. Time of onset ofNIDDM and genetic variation in the ß3-adrenoreceptor receptor gene. N Engl J Med1995;333;343-347.
  9. Hoffsted J, Wahrenberg H, Thorne A, Lonnqvist F. The metabolic syndrome is related to ß3-adrenoreceptor sensitivity in visceral adipose tissue. Diabetiologia 1996;39;838-844.14
  10. Tremblay J-F, Gougeon R. Meal- induced thermogenesis: effect of added ephedra and caffeine in subject with obesity and type II diabetes mellitus. McGill Nutrition and Food Science Center, Royal Victoria Hospital.
  11. Hedrei P, Gougeon R. Thermogenic effect of beta-sympathicomimetic compounds extracted from Citrus Aurantium, in humans. McGill Nutrition and Food Science Center,Royal Victoria Hospital.
  12. Zhi-Thin™ is a trademark of Bariatrix Products International Incorporated.
  13. Jacobs DO. Bioelectrical impedance analysis: implications for clinical practice. Nutrition in Clinical Practice 1997;12;204-10.
  14. Heymsfield SB, Nuñez C, Pietrobelli A. Bioimpedance analysis: what are the next steps? Nutrition in Clinical Practice 1997;12;201-3.
  15. Lukaski HC, Bolonchuk WW, Hall CB, Siders WA. J Appl Physiol 1986;60;1327-32.
  16. McClave, Snider. Indirect calorimetry: the search for clinical relevance. Nutrition in Clinical Practice 1992;7;203-6.
  17. PWEREXP BAR POWER THERM: by Bariatrix intl, Copyright Jones D.
  18. Brown D. Beckman glucose analyzer @ (operating manual). Beckman Instruments,Inc., 1981, Brea, CA.

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Advantra Z Ephedra


The differences between Citrus aurantium extract (Advantra Z®) and Ephedra extract

The alkaloids from Citrus species are biologically and physiologically distinct from those found in Ephedra, and possess properties that are not shared with the Ephedra alkaloids. The converse is also true; the Ephedra alkaloids possess properties that are not shared with the Citrus alkaloids. Scientifically, this is in part due to differences in pharmacokinetics and pharmacodynamics. The most obvious difference is that the Citrus alkaloids, unlike the Ephedra alkaloids, do not readily pass into the brain. The main factor governing the transfer of small molecules into the central nervous system is lipophilicity, and to quote from Wilkinson (2001):

“The distribution of drugs into the CNS from the blood is unique, because functional barriers are present that restrict entry of drugs into this critical site. One reason for this is that the brain capillary endothelial cells have continuous tight junctions; therefore, drug penetration into the brain depends on transcellular rather than paracellular transport between cells. The unique characteristics of pericapillary glial cells also contribute to the blood-brain barrier. At the choroid plexus, a similar blood-cerebrospinal fluid (CSF) barrier is present, except that it is epithelial cells that are joined by tight junctions rather than endothelial cells. As a result, the lipid solubility of the nonionized and unbound species of the drug is an important determinant of its uptake by the brain; the more lipophilic it is, the more likely it is to cross the blood-brain barrier. This situation often is used in drug design to alter brain distribution . . .”

As can be seen from the comparison of the structures of synephrine and octopamine with those of ephedrine and norephedrine, synephrine and octopamine (two of the five main alkaloids present in Citrus aurantium extract) both possess aromatic hydroxy substituents, which reduce their lipophilicity substantially, particularly because of their non-hindered para-orientation, and furthermore they lack the methyl substituent of the aliphatic sidechain which is characteristic of ephedrine and its congeners, thus further reducing lipophilicity.

The same comparison can be made between other Citrus and Ephedra alkaloids, but since synephrine itself predominates in the mixture that characterizes the extract(and is also in part converted to octopamine in the body) such further comparison is redundant (a figure showing the structures of the 5 main citrus alkaloids is appended).

As a consequence of their low lipophilicity, the Citrus alkaloids have no effects on the central nervous system (CNS) and since the CNS actions of the Ephedra alkaloids are responsible for at least some of the reported Ephedra side effects, the Citrus alkaloids are entirely incapable of causing similar side effects. In terms of effects in the periphery, while all the Citrus alkaloids are indirect-acting adrenergic agents, they are very much weaker than the Ephedra alkaloids. However, it has been shown that both synephrine and octopamine (the latter also present in the Citrus alkaloid mixture) can specifically and directly stimulate so-called β-3 receptors, the receptors believed to be mainly responsible for thermogenesis and lipolysis (the breakdown of stored fat).

The realization that there was a third type of adrenoceptor, in addition to the previously recognized β-1 and β-2 receptors, is fairly recent, having first been mooted in the late 1980’s and confirmed in the early 1990’s, but had been intimated by the work of Wenke et al. (1967) as long ago as the 1960’s. To quote verbatim from Wenke’s paper:

“By evaluating the dose-response relations in lipo-mobilizing sympathicomimetics, it can be shown that ” in the experimental conditions used ” these relations have a “simple” character in the oxedrines studied, a “quadratic” one in the used catecholamines. Only this represents the factic reality. For its explanation several attempts can be made; one of them is the model described here.”

Wenke further describes a complicated mathematical model which fits his results, but the simpler explanation is that the oxedrines used (which included synephrine and octopamine) act directly on β-3 receptors, while the catecholamines used have an indirect mechanism of action. The research of Wenke also suggests strongly that synephrine is much more potent than octopamine in activating β-3 receptors.

Galitzky et al. (1993), were the first to draw attention to the qualities of octopamine as a β-3 agonist. To quote from the English summary of this paper:

“These results suggest that octopamine is a specific endogenous ligand for β3-adrenoceptors in mammals”.

However, further work by this group (Carpene et al., 1999; Fontana et al., 2000) and by an independent group in Taiwan (Yen et al., 1998) has confirmed that octopamine is indeed a specific β3-agonist in mammalian cells. Taken together with the early observations of Wenke and his colleagues, observations made during the course of market surveillance, and the published work of Colker and his colleagues (Colker et al., 1999), it clearly indicates that synephrine and octopamine have unique properties that are not shown by the Ephedra alkaloids. It is obviously a property of considerable value in terms of losing weight (where the real objective is to eliminate unwanted fat) and in terms of making metabolizable substrates (fatty acids from stored fat) available as energy sources. In particular, Colker et al. showed that the weight of body fat lost in the subjects in their treatment group was greater than the actual measured loss of body weight:

In fact, the treatment group lost on average 3.1 kg of body fat, but only 1.4 kg of body weight. Since a gentle exercise program was part of the protocol for all groups, the only logical conclusion is that the subjects in the treatment group were gaining lean body mass as they lost fat mass. Such a conclusion is entirely consistent with the anticipated action of the mixture of alkaloids in Citrus aurantium extract; the specific fat-mobilizing actions of synephrine and octopamine against the general background of increase in the Resting Metabolic Rate caused by the indirect adrenergic effects of all the alkaloids.

The Chinese herb Zhi shi, which is the immature Bitter Orange (Citrus aurantium), is used to manufacture Citrus aurantium extract. This herb, Zhi shi, has been used in Chinese medicine for several centuries for a variety of purposes, including as a digestive aid, generally in doses of 3 – 15 grams as a decoction, but sometimes in doses as high as 45 grams.

The herb contains about 0.8% of mixed alkaloids, with synephrine predominating (the natural form of the alkaloid is l-synephrine), so the normal dose of 3 – 15 grams would provide 24 – 120 mg of Citrus alkaloids per dose, with an intake of as much as 360 mg not being unusual. There are no reports of side effects at these dosage levels. In addition to administering the herb itself as a decoction, extracts are also administered by the intravenous route in the treatment of shock, in doses equivalent to 10 – 40 grams (80 – 320 mg alkaloids). The following instructions come from Ou Ming (1989).

Similar instructions for use are found in other Chinese reference works.

Synthetic dl-synephrine is used therapeutically world-wide, often under the name oxedrine. The recommended dosage is 100 – 150 mg three times daily, with a maximum daily intake of 600 mg. At these dose levels the only reported side effects are rarely bradycardia (slowing of the heart rate; ephedrine, the main constituent of the Ephedra alkaloids, increases the heart rate) and exacerbation of narrow-angle glaucoma. Attached PDF files cover use of European specialties containing “oxedrine”, obtained from BIAM and the Compendium Suisse des Medicaments; an excerpt from the latter gives information on Sympalept® drops (Streuli, Switzerland):

Composition: Principe actif: tartrate d’oxédrine 100 mg.
Posologie/Mode d’emploi: Adultes 20 à 30 gouttes (100 à 150 mg) 3 fois par jour.

Prendre Sympalept environ ½ heure avant les repas à jeun. Administrer de préférence les gouttes non diluées sur un morceau de sucre.

Limitations d’emploi
Contre-indications: Allergie à l’oxédrine, thyréotoxicose, glaucome, troubles graves du rythme cardiaque, phéochromocytome, adénome de la prostate avec résidu urinaire et hypertension artérielle. Lors de la décompensation d’une insuffisance cardiaque ou d’une insuffisance coronarienne sévère, la seule prise d’oxédrine peut entraîner une aggravation de la situation cardiaque, y compris parfois un infarctus du myocarde.

Mesures de précaution: Une prudence particulière est de mise chez les patients qui présentent une artériosclérose, une insuffisance coronarienne, un infarctus récent du myocarde ou d’autres affections cardiaques et vasculaires organiques. Il convient en outre d’être prudent dans les tachycardies et/ou les troubles du rythme et chez les diabétiques. Débuter Sympalept à une posologie aussi faible que possible dans les affections rénales et hépatiques sévères. Après un arrêt brusque du traitement, il faut s’attendre à la possibilité d’une bradycardie et d’une chute tensionnelle. L’administration de doses élevées peut perturber la capacité de conduire un véhicule ou de manier des machines, du fait des modifications circulatoires et de l’action sur la capacité de réaction.

Effets indésirables: Une sensibilité particulière du patient et/ou une posologie élevée peuvent entraîner une agitation, une angoisse, une insomnie, des céphalées, un tremblement, des vertiges, une horripilation, des frissons et des palpitations, rarement également des accès sudoraux, des nausées et des vomissements. Il convient dans ces cas de réduire la posologie, d’interrompre ou d’arrêter le traitement.

Interactions: De nombreux médicaments, administrés de façon concomitante, peuvent agir sur les effets de l’oxédrine. On peut observer par exemple une majoration des effets après administration d’antidépresseurs tricycliques, d’inhibiteurs de la MAO, d’halotane et de cyclopropane, de médicaments à effets atropiniques, de théophylline et de ses dérivés, d’éthanol, de lévodopa ou d’ocytocine. Une atténuation des effets peut se voir par exemple après administration de phénothiazines, de b-bloquants (risque d’une bradycardie réflexe), de substances entraînant une alcalinisation des urines ou d’anti-hypertenseurs.

Surdosage: Un surdosage aigu accentue les effets indésirables mentionnés ci-dessus et peut occasionner en outre une élévation de la pression artérielle, une tachycardie, des extra-systoles ventriculaires et des crises d’angor. Ces symptômes régressent en règle spontanément et rapidement en raison de la demi-vie relativement brève du principe actif après l’arrêt du produit.

In comparison to the above, the single and daily intakes of alkaloids from most products based on Citrus aurantium extract are from 12 – 60 mg as a single dose, with 36 – 180 mg total daily intake!

To date, there have been at least five clinical studies performed with products containing Citrus aurantium extract in these dose ranges (Opus cit.; Kaats et al., 2002; Larocque et al., 2003; unpublished studies sponsored by Enforma, Herbalife and Nutratech), as well as several metabolic studies in human volunteers (Gougeon et al., ongoing studies which are in the process of being prepared for publication). There were no side effects observed in any of these studies. In particular, there were no effects seen on heart rate or blood pressure. Market surveillance covering many thousands of “user-days” has also failed to reveal adverse effects, thus indicating that Citrus aurantium extract is indeed a safe and effective alternative to Ephedra. Dr. Dennis Jones, M.A. (Cantab.), Ph.D. (Cantab.), C.Chem., FRSC(UK), C.Biol., M.I.Biol. August 4, 2003


  • BIAM (Banque de Données Automatisée sur les Médicaments):
  • Carpene, C., Galitzky, J., Fontana, E., Atgie, C., Lafontan, M. and Berlan, M., 1999, Selective activation of beta-3-adrenoceptors by octopamine; comparative studies in mammalian fat cells. Naunyn Schmiedebergs Arch. Pharmacol., 359, 310 – 321.
  • Colker, C.M., Kalman, D.S., Torina, G.C., Perlis, T. and Street, C., 1999, 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. Ther. Res., 60, 145 – 153.
  • Compendium Suisse des Medicaments:
  • Fontana, E., Morin, N., Prevot, D. and Carpene, C., 2000, Effects of octopamine on lipolysis, glucose transport and amine oxidation in mammalian fat cells. Comp. Biochem. Physiol. C., 125, 33 – 44.
  • Galitzky, J., Carpene, C., Lafontan, M. and Berlan, M., 1993, Stimulation spécifique des récepteurs β3-adrénergiques du tissu adipeux par l’octopamine, C.R. Acad. Sci. Paris, Sciences de la Vie, 316, 519, 523
  • Hedrei, P and Gougeon, R., 1997, Thermogenic effect of ß-sympathicomimetic compounds extracted from Citrus aurantium. McGill Nutrition and Food Science Center, Royal Victoria Hospital.
  • Kaats, G.R., Keith, S.C., Croft, H.A., Squires, W.G. and Pullin, D., 2002, in press.
  • Larocque, M., Gougeon, R., and Jones, D., 2003, manuscript in preparation.
  • Ou Ming, 1989, Chinese-English Manual of Common-Used in Traditional Chinese Medicine; Guangdong Science & Technology Publishing House and Joint Publishing (H.K.) Co., Ltd., Hong Kong, pages 348 – 349.
  • Pathak, B. and Gougeon, R., 1998, Thermic effect of Citrus aurantium in obese subjects. McGill Nutrition and Food Science Center, Royal Victoria Hospital.
  • Wenke, M., Lincova, D., Cernohorsky, M. and Cepelik, J., 1967, Some aspects concerning the structure-function relationship in lipomobilizing adrenomimetics. Arch. int. Pharmacodyn., 165, 53 – 63.
  • Wilkinson, G.R., 2001, Goodman and Gilman’s “The Pharmacological Basis of Therapeutics”, Tenth Edition, McGraw-Hill, page 10.
  • Yen, S.T., Li, M.H., Hsu, C.T., Lee, T.L. and Cheng, J.T., 1998, Stimulatory effect of octopamine on β3-adrenoceptors to lower the uptake of [14C]-deoxy-D-glucose into rat adipocytes in vitro. J. Autonomic Pharmacol., 18, 13, 19.

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Study Results


Synephrine Phramacokinetics And Cardiovascular Changes After Ingestion Of Citrus Aurantium Dietary Supplements

C. A. Haller, MD, M. Duan, P. Jacob III, PhD, N. L. Benowitz, MD, University of California, San Francisco, San Francisco, CA

BACKGROUND: Ephedra-free weight loss dietary supplements (DS) containing Citrus aurantium (CA), a botanical source of the adrenergic amines synephrine (SYN) and octopamine, have rapidly replaced banned ephedra products, but have not been adequately studied. These DS may have some of the health risks associated with ephedra. We present novel data on CA PK/PD in humans.

METHODS: In a randomized, double blind, placebo-controlled crossover study, 10 healthy adults took 1 oral dose of CA alone (Advantra Z®, (ADV) with 45 mg SYN), and a multi-component DS (Xenadrine EFX® (XEN) with 5.5 mg SYN), with a 1-week washout between treatments. Plasma drug levels were measured over 12 hours by LC-MS/MS.

RESULTS: XEN but not ADV increased systolic and diastolic BP with peak changes over placebo at 2 hrs of 9.6 _ 6.2 mm Hg systolic (p _ 0.047), and 9.1 _ 7.8 mm Hg diastolic (p _ 0.002). Heart rate was increased at 6 hrs (16.7 bpm with XEN, p _ 0.011; 11.4 bpm with ADV, p _ 0.031). SYN Cmax was 2.8 ng/ml with ADV and 0.35 ng/ml with XEN. Caffeine Cmax was 5.1 mcg/ml with XEN. Plasma levels of octopamine were negligible. Dose-adjusted SYN PK were similar between treatments with tmax _ 90 min, t1/2 _ 3.0 hrs, V/F _ 16347L, and CL/F _ 88.9 L/min for XEN.

CONCLUSIONS: Ephedra-free weight loss DS have significant cardiovascular stimulant actions. These pressor effects are not likely caused by CA, since a 8-fold higher dose of synephrine (ADV) had no effect on blood pressure, but may be attributable to caffeine and other stimulants in the DS.

© American Society for Clinical Pharmacology and Therapeutics

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Mechanism Of Effects


Slimirex Information: Advantra Z Mechanism of Effects

Since the amines in Advantra Z® are not as lipophilic as those in ma huang/ephedra, they do not readily cross the blood/brain barrier. In fact, the unique amine composition in Advantra Z® prefers retention in the periphery rather than passage into the brain.

No FlashAdditionally, research shows that Advantra Z® stimulates beta-3 cell receptors with minimal impact on alpha 1,2 and beta 1,2 receptors, which means that Advantra Z® increases the metabolic rate (Thermogenesis) without affecting heart rate or blood pressure unlike ma huang/ephedra.

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