Over Citrus aurantium for circulation three hour time circluation following ingestion of the product significant increases Ckrculation resting oxygen uptake and caloric expenditure were occurred. However, these effects on heart rate and blood pressure were small and have not been observed in other studies. Diabetes Metab J.

Citrus aurantium for circulation -

Brown adipose tissue respiration was determined as previously described 40 , 41 with minor modifications. BAT was prepared for measurements of respiratory flux rates by mechanic dissection with sharp forceps in relaxing buffer BIOPS; in mM: CaK2EGTA 2.

After that, the interscapular brown adipose tissues were washed in ice-cold respiration medium MIR05—in mM: EGTA 0. The respiratory rates of BAT were determined with the Oroboros 2k-Oxygraph Oroboros Instruments, Innsbruck, Austria in 2 ml of MIR05 at 37°C with continuous stirring.

Before adding the tissue into the chamber, wet weight measurements were taken, and a sample of 5—7 mg was used per chamber.

All measurements were taken at oxygen concentrations above nmol ml-1 in the chamber. DatLab software Oroboros Instruments, Innsbruck, Austria was used for data acquisition and analysis. Digitonin is used to permeabilize the cell membranes while leaving the mitochondrial membranes intact because of its specificity for solubilizing cholesterol, which exists in much higher concentrations in the plasma membrane.

The study was carried out with two groups of independent substrates in each chamber: chamber A, in mM glutamate 10, pyruvate 5, malate 2, ADP 1 and succinate 10, for the analysis of carbohydrate-related oxidation with electron entry through complexes I and II of the respiratory chain and chamber B, in mM palmitoyl-carnitine 0.

The addition of cytochrome c 10 μM allowed for the evaluation of the integrity of the mitochondrial membrane because an increase in respiration with the addition of cytochrome c indicates a defect in the outer mitochondrial membrane Statistical analyses were performed using GraphPad Prism software version 6.

The body weights of normal litters NL and small litters SL during lactation PND21 are shown in Figure 2. The small litter group SL had a higher body weight than the normal litter group NL on PND4 until weaning PND21, SL: 3.

NL: 2. Figure 2. Evolution of body weight during the lactation period 21 days of mice raised in normal NL and small SL litters.

The SL group had a higher body weight NL: SL: SL: 3. aurantium and synephrine did not show significant differences in fat mass with the NL groups Figure 3D. Figure 3. Effect of treatments with C. aurantium and synephrine on body weight A,C , body composition by Nuclear Magnetic Resonance B,D and tissue weight of visceral WAT E and BAT F of mice raised in normal and small litters in the pre-treatment A,B and post-treatment C—F period.

NL A,B. NL-Syn C,D. SL-Syn E,F. The accumulated body weight from PND30 to PND49 is depicted in Figure 4. The SL groups treated with C. Figure 4. Accumulated weight gain of mice raised in normal and small litters submitted to treatment with C.

There was no significant difference in heart rate Supplementary Figure 1A , systolic blood pressure Supplementary Figure 1B , and diastolic blood pressure Supplementary Figure 1C in the normal and small litter groups treated with C.

aurantium and synephrine or vehicle. There was no significant difference in the OGTT Supplementary Figure 2A or the area under the curve AUC of the OGTT Supplementary Figure 2B in the normal and small litter groups treated with C.

The plasma concentration of leptin in the SL groups treated with C. aurantium and synephrine was not different from that in the NL groups or SL vehicle group Figure 5A. Figure 5. Effect of treatment with C.

aurantium and synephrine in hormonal dosages. Plasma leptin A , Total T3 B and Free T4 C. There was no significant difference in the absolute catecholamine content in the adrenal gland Figure 6A. There was no significant difference in plasma corticosterone Figure 6C.

Figure 6. aurantium and synephrine on the medulla adrenal and plasma corticosterone. aurantium and synephrine 2-fold-increase vs. NL -Syn; 2-fold-increase vs. Treatment with C. aurantium and synephrine was able to restore the lipid droplet size and quantity of nuclei in the small litter groups.

Figure 7. BAT histology by Hematoxylin—Eosin HE staining with 40× magnification. Quantitative analysis of lipid droplets and nucleus number of the BAT. Figure 8 shows biomarkers related to thermogenesis in BAT. The NL groups did not show differences in gene expression in BAT. aurantium and synephrine showed increased gene expression of UCP-1, PRDM16, PGC-1α, and PPARγ.

Treatment of the SL group with C. SL groups treated with C. The SL-Syn group showed higher relative mRNA expression of PRDM than the SL and NL groups 2. No significant difference was observed in the gene expression of CPT Figure 8D , ADRβ-3 Figure 8E , or BMP7 Figure 8G.

However, treatment with C. Figure 8. aurantium and synephrine on thermogenic factors in BAT. Also, SL-Syn group presented no changes in all parameters of BAT mitochondrial function evaluated. Figure 9. High resolution respirometry of brown adipose tissue from overfeed mice.

Flux per mass with substrates pyruvate, glutamate, malate, and succinate A. Flux per mass with substrates palmitoyl-L-carnitine, malate, and ADP B. It is well known that overfeeding early in life causes metabolic effects in the short- and long-term, but such effects are poorly investigated in adolescence.

The reduction in litter size is an effective and reproducible model of obesity 12 , 15 , Our results demonstrated that both overweight and metabolic changes typical of obesity persist from lactation to adolescence.

Moreover, the administration of Citrus aurantium or its active compound, synephrine, proved efficacious in ameliorating certain metabolic dysfunctions induced by postnatal overfeeding, employing distinct mechanisms.

Conceicao et al. We find at PND30, overweight and high body fat in SL group by body composition NMR analyses. Furthermore, we showed that the SL group showed higher body weight from PND4 until adolescence. Studies were carried out upon utilization of products derived from medicinal plants and nutraceuticals for the management of obesity and metabolic disorders Until this moment, no studies have demonstrated the effects of C.

aurantium and synephrine at the same doses and period adolescence used in the current investigation. Here, we used a smaller dose than the one usually used in other studies because it would not be interesting to use elevate adrenergic agonist dose in adolescent animals.

Hansen and collaborators 30 demonstrated, in adult female rats, that the administration of C. In agreement, we also observed that the SL group treated with C. aurantium or synephrine did not show significant differences in body weight and body fat on PND Synephrine, due to it is an adrenergic agonist effect and its similarity to ephedrine, has potential adverse effects upon the cardiovascular system However, we did not show changes in heart rate or systolic or diastolic blood pressure in the treatments with C.

aurantium extracts and synephrine. Citrus aurantium has been associated with improvement in hyperglycemia Although obese, the SL group had no changes in glucose homeostasis, with no significantly different in TOTG compared to the NL group.

Litter size reduction programming impairs leptin signaling and causes leptin resistance at PND 37 , Corroborating these findings, the SL group showed hyperleptinemia, indicating leptin resistance in these animals as early as 50 days old.

However, C. aurantium and synephrine slightly reduced this hyperleptinemia induced by overfeeding. In the literature, no studies were found about the effect of C.

aurantium and synephrine on leptin secretion and signaling. Thus, precocious treatment with C. aurantium may prevent those animals from developing future glucose intolerance since leptin resistance can be one contributor factor to insulin resistance.

Rodrigues and collaborators 37 showed that, in PND21, the SL group had high TSH and serum thyroid hormone concentrations. However, on PND, this group showed normal TSH and lower T3 and T4 in serum. Here, treatment with C. aurantium increased total T3 and free T4 compared to all NL groups in this study, and synephrine SL-Syn increased even more because it was higher than in the SL group.

As there are no studies focusing the interplay between thyroid function and C. aurantium or synephrine , more studies are needed to better understand the mechanisms involved.

aurantium , other than synephrine, can increase adrenal catecholamines, which can occur either by greater synthesis or by accumulation due to deficient secretion.

We measured only tissue catecholamines, and this increase was not enough to alter cardiovascular parameters. However, this change may have resulted in a slight increase in circulating adrenaline, inducing lipolysis in white and brown adipocytes, through their interaction with β-3 adrenergic receptors Only one in vitro study has reported the influence of C.

aurantium on the differentiation and activation of brown adipocytes through anti-adipogenic and thermogenic mechanisms In the current study, we explored the in vivo anti-obesity potential of C.

aurantium extracts and its main active component, synephrine, in brown adipose tissue dysfunction of adolescent mice programmed by early postnatal overfeeding. The whitening of BAT occurs in obesity. In this process, BAT has increased tissue mass with large lipid droplets, low vascularization, high pro-inflammatory cytokine expression, and low UCP-1 and other thermogenesis marker expression 13 , 48 , causing dysfunction.

In the qualitative and quantitative analyses of BAT, we demonstrated a reduction in its mass and in the content of lipid vesicles and an increase in the number of nuclei in the SL groups treated with C. aurantium and synephrine, showing that the treatments normalized the BAT structure and recovered its original phenotype.

We investigated some important markers of thermogenesis and activity in BAT, such as UCP-1, PRDM16, PCG-1α, CPT-1, beta-3AR, PPARγ, and BMP-7 Furthermore, we found, in general, higher gene expression of UCP1, PRDM 16, PGC-1α, and PPARγ, demonstrating the thermogenic action of both C.

aurantium and its active compound, synephrine. β-3 adrenergic receptor expression in BAT was unchanged, but we cannot ignore the effect of synephrine β-3 adrenergic ligand on adrenergic receptors.

PPARγ is responsible for positively regulating genes involved in lipid oxidation CPT-1 and thermogenesis, such as UCP-1 and PGC-1α responsible for mitochondrial biogenesis and stimulation of UCP-1 gene expression In addition, PPARγ participates in several physiological functions, such as glucose metabolism control, adipocyte differentiation regulation, and inflammatory response regulation.

This receptor is considered a primary regulator of adipogenesis, controlling cell differentiation of preadipocytes into mature adipocytes 51 and acting in the direction of white and brown adipocyte differentiation UCP-1 is a key marker of thermogenesis in BAT.

In experimental models, the absence of UCP-1 is associated with increased body weight and decreased thermogenesis in BAT In our model of obesity induced by litter size reduction, we observed BAT dysfunction and UCP-1 gene expression reduction.

aurantium on BAT was better than synephrine alone that only caused a higher gene expression for PRDM16, a known transcriptional co-regulator capable to directing brown adipogenesis. Mitochondria primarily produce ATP for cellular energy by directing proton flow to ATP synthase.

This occurs when protons, temporarily stored in the intermembrane space, are released into the mitochondrial matrix by uncoupling proteins, reducing the membrane potential, and producing heat rather than ATP Thus, the induced decrease in proton flux is mediated by an increase in UCP1 in adipose tissue, increasing heat production and potentiating weight loss.

This mechanism is important as a therapeutic target in the regulation of body weight. Considering the higher expression of UCP1 in BAT, this could be one of the mechanisms of action of C.

UCP-1 activity is mainly regulated by fatty acids that represent the main energy substrates for oxidation during thermogenesis, providing NADH and FADH2 to supply the respiratory chain and ensure the proton gradient Isolated synephrine, in turn, did not change oxygen consumption in relation to the energy substrates studied.

In general, C. aurantium and synephrine increased thermogenic marker expression in BAT without modifying the cardiovascular system. The modern obesogenic environment can significantly increase obesity worldwide, especially in adolescence This period is a crucial stage of human development when several psychological and social changes occur in addition to the acquisition of new life habits that are the foundation for health and wellbeing in adulthood Our results indicate that obesity treatment in the critical period of adolescence, when the neurological system is particularly sensitive to interventions, can be a good therapeutic strategy.

Even when using C. aurantium or synephrine at a low dose, both showed beneficial effects, reducing adipose tissue mass, and improving BAT functionality without impacting blood pressure and glucose homeostasis. With due care in extrapolating therapy from animals to humans, the set of our findings suggest that therapeutic use of these compounds can improve the metabolic profile of obese adolescents without adverse cardiovascular side effects.

Further studies are necessary to better evaluate the safety of using both C. The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The animal study was approved by the Animal Care and Use Committee of the Biology Institute of the State University of Rio de Janeiro. Participants were between 18 and 30 years of age, had a body mass index BMI between Through screening, we studied the presence of some conditions that would make them ineligible to participate in the study, for instance, smoking, present and past anabolic steroid usage, cardiorespiratory, neurological or musculoskeletal disorders, use of pharmacotherapies that affect the autonomic nervous system.

At the end of the study, the sample consisted of 12 subjects Figure 1. Additionally, baseline values of heart rate beats per minute , systolic blood pressure SBP , and diastolic blood pressure DBP mmHg were logged Table 1.

Table 1. Mean values followed by their respective standard deviations minimum and maximum of age, mass, height, BMI, heart rate, SBP and DBP. The intervention protocols were split into three phases, with an interval of 48—72 h between each protocol to provide time for the participants' physical recovery.

On the first day, an initial interview was completed with the participating candidates in the study. After screening, eligible applicants were provided with a list of guidelines to abstain from certain citrus fruits mandarin, sweet, and bitter orange , alcoholic and caffeinated beverages, or nutriments coffee, sports drinks, chewing gum, chocolate , and exercise 24 h prior to the ensuing study sessions.

Participants were told to have a light meal e. Through a random sequence, in the second step, participants were randomized to consume a capsule containing mg C. This amount was selected as it is regularly applied in clinical practice In the final stage, the participants received the protocol contrary to the previous one to safeguard the study's crossover.

An independent researcher who did not participate in the data logging was responsible for randomizing the interventions, choosing the capsules, and assigning them to the investigator. The capsules were opaque and visibly identical; neither the participant nor the investigator could recognize the capsules' contents.

The capsules were attained in commercial form from a reliable provider Florien Fitoativos ® Ltd. Naringin and hesperidin concentrations were not analyzed.

The participants persisted for 20 min walking at this speed, and at the end of the activity, the participants were once more seated and monitored for an additional 60 min 8. SBP and BPD measurements were completed indirectly using a stethoscope Littman Classic II, Saint Paul, USA and aneroid sphygmomanometer Welch Allyn Tycos, New York, USA on the participants' left arm For HR and HRV indices scrutiny, cardiac activity was logged beat by beat throughout the data logging technique with a sampling rate of 1 kHz using a Polar ® heart rate monitor model RSCX.

The HR and HRV recordings were logged at the following epochs: Rest R1: 90th to 95th min of resting after capsule ingestion , and all through exercise recovery: 0 to 5th min; 5th to 10th min; 15th to 20th min; 25th to 30th min; 35th to 40th min; 45th to 50th min, and; 55th to 60th min Figure 2.

Series with regular heartbeats R-R intervals were required to make the HRV indices, as recommended by the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology In these series, digital and manual filters were executed to remove artifacts.

After collection, the RR intervals were exported to the software program Kubios ® HRV Analysis to produce the linear indices of the frequency domain and time domain Frequency domain analysis was accomplished via spectral analysis by means of the Fast Fourier Transform FFT to cause the high frequency HF index with a sampling rate of 0.

The non-linear HRV analysis was achieved using the PyBios ® software Biomedical Signal Analysis in Python Version 1. We dispersed the number of RR intervals through six levels 0—5 , transforming them into a spatial methodology; a sequence of three symbols. All patterns were independently assembled into two clusters, according to the number and type of variation between symbols:.

A pilot study conducted with six participants performed the sample size calculation. We applied the root mean square of successive differences between RR intervals in the online software at www. br , which provided the magnitude of the difference.

We measured a standard deviation of The Shapiro-Wilk statistical test was enforced to assess data normality. For the cardiovascular recovery and autonomic reactivity analysis during the experimental protocols Rest vs.

recovery , One-way analysis of variance ANOVA1 for repeated measures and the Bonferroni post-test was enforced when the assumption of data normality was attained. Friedman's test followed by Dunn's post-test was required for data that did not acquire a normal distribution. Cohen's d calculated effect sizes to measure the magnitude of changes for significant differences.

Assessments were achieved using Statistical Package for the Social Sciences SPSS IBM ® SPSS Statistics v. The descriptive data of twelve healthy males that met the study criteria are included in Table 1.

These datasets strengthen the homogeneity of our sample. The HR recovery analysis revealed no significant differences between the protocols. In the placebo protocol, the comparison of resting and after exercise established an increase in HR from 0 to 5th min of recovery Rest vs.

In the C. aurantium protocol, the same results were attained, and HR values remained significantly enlarged from 0 to 5th min of recovery Rest vs. Table 2. No significant changes were identified in the C.

aurantium intervention during the recovery analysis rest vs. recovery for DBP, MAP, and PP. Only SBP demonstrated significant changes in 1 min following exercise Rest vs. aurantium protocol. During the placebo protocol, SBP remained significantly higher during 3 min of recovery compared to rest Rest vs.

Table 3. Time and frequency domain indices in addition to non-linear analyzes revealed that autonomic heart rate recovery occurred more quickly in the C. aurantium protocol compared to the placebo protocol. In the placebo protocol, the investigation of recovery rest vs. recovery of the HF index revealed that its values remain depressed throughout 10 min of recording after exercise Rest: Figure 3.

In the placebo protocol, pNN50 index values continued to be significantly decreased throughout 20 min of recovery related to resting values Rest: Our findings demonstrate that the ingestion of C. aurantium p-synephrine mg prior to exercise fast-tracks the fall in SBP after physical exertion.

Earlier studies propose that one of the benefits of using C. aurantium equated to other adrenergic substances e. Activation of β-3 adrenergic receptors triggers reverse inotropic effects, antagonizing the activation of further classes of adrenoreceptors β-1 and β-2 in cardiac tissue and, thus, decreasing sympathetic modulation to the heart.

This clarifies why overall, the binding of p-synephrine with β-3 adrenergic receptors does not increase BP or HR, displaying cardioprotective effects In this study, in the placebo intervention, for the spectral analysis, the HF index, representative of parasympathetic modulation, needed 10 min after termination of exercise to recover.

aurantium protocol, we did not find substantial changes in the HF index in exercise recovery vs. Analogous deviations occurred in the pNN50 index and were reduced 20 min after cessation of exercise in the placebo protocol. While in the protocol with C. aurantium , this index continued to be reduced for only 10 min after exercise.

aurantium protocol, transformations were only following 5 min of recovery. However, in the C. aurantium protocol, the values were only meaningfully reduced for 5 min after the cessation of exercise. These observations make C.

aurantium a safe nutritional compound to be applied during exercise, which supports the recovery of autonomic parameters following exercise.

Since a slow post-exercise autonomic recovery is linked with an increased cardiovascular risk 25 , the results of our study indicate that C. aurantium compounds have a potential preventive role on the onset of cardiovascular complications in physical exercise.

As caffeine and C. aurantium are frequently sold as complementary formulas for use in humans, preceding studies have assessed the effects of using these substances alone and in combination. Through a randomized clinical trial, Guitiérrez-Hellín et al. aurantium alone or in combination with caffeine would have different results for fat utilization during aerobic physical exercise.

No superiority was found between C. aurantium alone and combined with caffeine on the total values of fat consumption during the physical exercise session, while both interventions were superior to the placebo treatment.

This supports the isolated use of C. aurantium an alternate way to be applied as an adjunct in cutting body fat without inducing cardiac risk. In the study by Guitiérrez-Hellín et al. aurantium isolated supplement. In contrast, the HR and SBP were significantly higher when caffeine was included in the formulation.

Our study achieved no changes for HR, and SBP was lessened more quickly following exercise. The identification of β-3 adrenoreceptors in cardiovascular tissues posed challenges to the paradigm of sympathetic regulation by β-1 and β-2 adrenoceptors.

The binding response of p-synephrine to the β-3 receptor may elucidate why no increase in HR or BP is detected when C. aurantium is enforced alone. In contrast, when C. aurantium is combined with caffeine in dietary supplements, it is capable of affecting these parameters, particularly in caffeine-sensitive individuals It has been revealed that the combination of these substances promotes a significant increase in the concentration of plasma catecholamines e.

The study by Kliszczewicz et al. aurantium upsurges sympathetic modulation to the heart throughout rest and corroborates the increases in HR and SBP achieved in the study by Guitiérrez-Hellín et al.

It is assumed that caffeine alone can increase HR during physical exercise Despite that, a recent meta-analysis demonstrated that caffeine could not delay vagal return to the heart after exercise, evaluated by the HF and root mean square of successive differences between RR intervals RMSSD indices Equally, Kliszczewicz et al.

aurantium combined. Caffeine and C. aurantium combination have no extra effects on exercise fat utilization 5. These substances appear to exhibit the opposite cardiovascular effects and, thus, caffeine seems to overlap the beneficial effects of the isolated use of C.

aurantium on cardiovascular health. In this study, C. Many weight loss supplements use bitter orange extracts in combination with other ingredients. However, scientific studies have not thoroughly examined the composition of these supplements to determine which ingredient, if any, supports weight loss.

Notably, p-synephrine has been shown to increase fat breakdown, raise energy expenditure, and mildly suppress appetite , all of which may contribute to reduced weight.

Yet, these effects occur at high doses that are discouraged due to the lack of safety information 4 , 8 , Bitter orange and its extracts are used in Traditional Chinese Medicine TCM to treat indigestion, diarrhea, dysentery, and constipation.

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

Several sports organizations, such as the National Collegiate Athletic Association NCAA , list synephrine as a stimulant. Furthermore, one study determined that bitter orange juice contains furanocoumarin, a compound that may cause the same medication interactions as grapefruit juice Therefore, people taking decongestants or those who have high blood pressure, an irregular heartbeat, or glaucoma should avoid the juice and fruit of bitter oranges.

Despite numerous studies showing that bitter orange extracts are not stimulants, widespread controversy exists, and the NCAA has listed it as a banned substance. Bitter orange may also interact with certain medications.

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

In another study, eating a whole bitter orange containing Still, people who are pregnant or breastfeeding should avoid bitter orange due to a lack of safety information 1.

Bitter orange is likely safe in doses ranging from The juice of the bitter orange can be used as a marinade to flavor fish and meat. Bitter orange has several other household uses outside of the kitchen. These include 2 :.

Bitter orange is a citrus fruit with several household and industrial uses, ranging from food additives to perfumery. You may want to avoid this fruit and its extracts if you have high blood pressure, an irregular heartbeat, or glaucoma.

Likewise, bitter orange supplements are banned for NCAA athletes. Our experts continually monitor the health and wellness space, and we update our articles when new information becomes available.

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Background: There are still Mindful eating and self-compassion studies of the Citrus aurantium for circulation safety of the Circulatino use of Ciyrus Citrus aurantium for circulation in aerobic uarantium exercise. Objective: To evaluate firculation effect of C. aurantium supplementation on the Cigrus 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. No unfavorable cardiovascular effects were achieved for HR, DBP, PP, and MAP parameters.

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Wednesday LIVE stream with Rvdebs Happy Valentines Day! Introduction Cihrus aims: Citrus aurantium for circulation is a multifactorial condition with high ror Alternative anti-depressant therapies, associated with important chronic disorders such circuulation diabetes, dyslipidemia, Citrjs cardiovascular dysfunction. Citrus corculation L. Antispasmodic Foods and Diet is a medicinal plant, and its active component, synephrine, a β-3 adrenergic agonist, can be used for weight loss. We investigated the effects of C. aurantium and synephrine in obese adolescent mice programmed by early postnatal overfeeding. Methods: Three days after birth, male Swiss mice were divided into a small litter SL group 3 pups and a normal litter NL group 9 pups.

Citrus aurantium for circulation -

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 ]. As a consequence, an increase in heart rate after two to three half-lives when the p- synephrine blood levels will have dropped to one-fourth to one-eighth the peak blood levels would not be expected.

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

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

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

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

When caffeine was added, increases in heart rate and blood pressure were observed [ 46 ]. These studies indicate that in rats at very high doses of p -synephrine the combination with caffeine may result in cardiovascular effects. However, due to the highly inequivalent dosing between this study in rats and typical dosing in humans, the results of this study in rats cannot be directly extrapolated to humans.

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

These same β-3 adrenergic receptors are also associated with cardiovascular tissues, and their activation results in a down-regulation of cardiovascular stimulation [ 48 , 49 ]. Thus, p -synephrine stimulation of β-3 adrenoreceptors in the cardiovascular system does not result in an increase in blood pressure or heart rate but may exhibit a modulating rather than a stimulatory effect.

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

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

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

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

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

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

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

All authors have served as consultants for Nutratech, Inc. Nutratech Inc. provided some of the unpublished research reports. Chen JK, Chen TT. Zhi Shi Fructus Aurantii Immaturus. Chinese Medical Herbology and Pharmacology.

City of Industry, CA USA: Art of Medicine Press. Stohs SJ, Shara M. A review of the safety and efficacy of Citrus aurantium in weight management. In: ed. Bagchi D, Preuss HG. Obesity: Epidemiology, Pathophysiology, and Prevention.

Boca Raton, FL, USA: CRC Press. Pellati F, Benvenuti S. Chromatographic and electrophoretic methods for the analysis of phenethylamine alkaloids in Citrus aurantium. J Chromatog A. Sander LC, Putzbach K, Nelson BC.

et al. Certification of standard reference materials containing bitter orange. Analyt Bioanalyt Chem. Evans RL, Pho AN, Roman MC, Betz JM. Penzak SR, Jann MW, Cold JA.

Seville sour orange juice: synephrine content and cardiovascular effects in normotensive adults. J Clin Pharmacol. Bent S, Padula A, Neuhaus J. Safety and efficacy of Citrus aurantium for weight loss. Amer J Cardiol. Nasir JM, Durning SJ. Exercise-induced syncope associated with QT prolongation and ephedra-free Xenadrine.

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

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

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

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

Amer J ClinNutr. Kendall-Reed P. Study on the effectiveness of Ultra Slim Down ® for the reduction of body weight.

Unpublished report. Kalman DS, Oxford S, Schwartz HI, Krieger DR. A double blind clinical evaluation of the metabolic effects of Xenadrine EFX TM compared to two ephedra-containing products in normal healthy volunteers.

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

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

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

An acute clinical trial evaluating the cardiovascular effects of an herbal ephedra-caffeine weight loss product in healthy overweight adults. Int J Obes.

Kalman DS. Comment on: An acute clinical trial evaluating the cardiovascular effects of an herbal ephedra-caffeine weight loss product in healthy overweight adults.

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

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

Haller CA, Benowitz N, Peyton J III. Hemodynamic effects of ephedra-free weight loss supplements in humans. Amer J Med. Bui LT, Nguyen DT, Ambrose PJ.

Blood pressure and heart rate affects following a single dose of bitter orange. Ann Pharmacodyn. Sale C, Harris RC, Delves S, Corbett J. Metabolic and physiological effects of ingesting extracts of bitter orange, green tea and guarana at rest and during treadmill walking in overweight males.

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

J Int Soc Sports Nutr. Citrus aurantium extract has no effect on blood pressure or heart rate in healthy adults. Unpublished report Talbott SM, Christopulos AM, Richards E. Haller CA, Duan M, Peyton J III, Benowitz N. Human pharmacology of a performance-enhancing dietary supplement under resting and exercise conditions.

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

Effects of p -synephrine alone and in combination with selected bioflavonoids on resting metabolism, blood pressure, heart rate and self-reported mood changes.

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

Presented at the annual meeting of the American College of Nutrition. Abstract No. Bloomer RJ, Canale RE, Blankenship MM. They work by deactivating free radicals, which are unstable compounds that damage your cells, increasing inflammation and your disease risk 15 , Protoalkaloids are plant compounds found in bitter orange that have anti-inflammatory and antiviral properties.

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

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

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

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

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

Despite numerous studies showing that bitter orange extracts are not stimulants, widespread controversy exists, and the NCAA has listed it as a banned substance. Bitter orange may also interact with certain medications.

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

In another study, eating a whole bitter orange containing Still, people who are pregnant or breastfeeding should avoid bitter orange due to a lack of safety information 1.

Bitter orange is likely safe in doses ranging from The juice of the bitter orange can be used as a marinade to flavor fish and meat. Bitter orange has several other household uses outside of the kitchen. These include 2 :. Bitter orange is a citrus fruit with several household and industrial uses, ranging from food additives to perfumery.

You may want to avoid this fruit and its extracts if you have high blood pressure, an irregular heartbeat, or glaucoma. Likewise, bitter orange supplements are banned for NCAA athletes. Our experts continually monitor the health and wellness space, and we update our articles when new information becomes available.

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Medically reviewed by Adrienne Seitz, MS, RD, LDN , Nutrition — By Amber Charles Alexis, MSPH, RDN on March 17,

Ayrantium orange Citrus aurantium Alternative anti-depressant therapies, aruantium known as Thermogenic weight loss results orange aurantkum Seville circulztion, is a citrus fruit with a multitude of uses. This Alternative anti-depressant therapies auranyium all you need to know about bitter orange, including its role in weight Alternative anti-depressant therapies and skin health, as well as its overall safety as a supplement. The bitter orange plant thrives in subtropical regions but can withstand adverse environmental conditions like frost for short periods 2. Oval or oblong in shape, the fruit is red-orange when ripe and has a distinctively thick, dimpled skin. There are 23 cultivars of the fruit, the most prominent of which is Bergamot. You can expect some varieties to be more bitter than others.