SEARCH

SEARCH BY CITATION

Keywords:

  • Body weight;
  • Citrus aurantium;
  • RCT;
  • synephrine alkaloids

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Conflicts of interest
  9. References

Numerous herbal supplements are presently marketed as weight-loss aids, but the efficacy of most is not proven. One such supplement is the extract of Citrus aurantium (bitter orange). The objective of this systematic review is to critically evaluate the evidence of efficacy for C. aurantium and weight management. Electronic databases, conference proceedings and pertinent journals were searched for relevant RCTs. Bibliographies and our departmental files were searched also. No restrictions on date or language of publication, age of participants or duration of treatment were imposed. Two reviewers independently determined the eligibility of studies, extracted data and evaluated the methodological quality of included studies. Seven studies were identified, of which four met the inclusion criteria. All RCTs had major methodological flaws. Two RCTs reported a marginal to statistically significant reduction in body weight and body fat in participants treated with C. aurantium-containing supplements, when compared to placebo. One trial reported a statistically significant reduction in body fat only, while the other reported a statistically significant increase in body weight. Adverse events included anxiety, elevated heart rate and musculoskeletal complaints. The evidence of efficacy for C. aurantium and weight management is contradictory and methodologically weak. Until more rigorous RCTs emerge, C. aurantium cannot be recommended as a treatment for weight loss.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Conflicts of interest
  9. References

Overweight and obesity have become major public health problems.1,2 Conventional management strategies are efficacious but, due to poor compliance, often not effective. Many herbal supplements with purported weight-loss benefits are available, but their efficacy have not been proven. One such supplement is bitter orange.

Citrus aurantium is the Latin name for bitter orange, also known as sour orange or Seville orange.2 The fruit and the constituents of the herb are used in food and cosmetic products, but it is the plant extract that is widely used in medicinal products.2,3C. aurantium contains alkaloids that have adrenergic properties. In fact, the active ingredients in C. aurantium, synephrine and the tyramine metabolite octopamine, are similar in structure to epinephrine and norepinephrine, respectively.3 Because of its adrenergic properties, C. aurantium-containing products are clinically used as nasal decongestants,4 as well as for ophthamological procedures.5

C. aurantium also has been postulated to cause weight reduction. This is thought to be due to its action on alpha and beta adrenergic receptors, resulting in a decrease in gastric motility and hunger.6 The synephrine alkaloids (SA) in C. aurantium also have been demonstrated to increase fat metabolism via the stimulation of beta-adrenergic receptors.7

The effects of SA on body weight in animals are well documented,7,8 and clinical trials involving the use of SA for body weight reduction have been conducted. A previous systematic review concluded that C. aurantium supplementation did not result in any clinically significant weight loss.9 However, further trials involving C. aurantium supplementation have subsequently emerged. This, and the fact that the use of C. aurantium and SA in weight-loss supplements became popular after the US Food and Drug Administration (FDA) banned the use of Ephedra/ephedrine-containing dietary supplements,2,3 makes a new systematic review necessary.

The objective of this systematic review is to examine the evidence of efficacy for herbal supplements containing C. aurantium or SA in reducing body weight of human patients or volunteers, using data from RCTs.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Conflicts of interest
  9. References

Electronic searches were conducted in the following databases: MEDLINE, EMBASE, AMED, CINAHL, and The Cochrane Library. Each database was searched from inception to April 2011. The search terms used included: dietary supplement, herbal supplement, nutritional supplement, nutraceutical, anti-obesity agent, appetite suppressant, overweight, obesity, weight loss, slimming, body weight, body fat, body mass index, Citrus aurantium, bitter orange, Seville orange, sour orange, bigarade orange, petigrain, bergamot, zhi shi, neroli oil, marmalade, synephrine, phenylephrine, and derivatives of these. We also searched the Internet for relevant conference proceedings and hand searched relevant medical journals, as well as our own files for any unpublished studies or abstracts. The bibliographies of all located articles were also searched. No restrictions on date or language of publication, age of participants or duration of treatment were imposed.

Because we set out to evaluate the efficacy of C. aurantium and SA, only double-blind, randomised, placebo-controlled trials were included. To be considered for inclusion, RCTs had to test the efficacy of orally administered herbal supplements containing C. aurantium extracts or SA for body weight or fat reduction in overweight or obese human volunteers. studies had to report body weight or body composition as outcome measures. Any RCTs were included irrespective of whether or not they incorporated adjustments in the participants' lifestyle (e.g. dietary restriction and exercise) or other co-interventions into the trial regimen. However, any such interventions had to be applied equally to both the supplement and placebo groups.

Two reviewers (IO and LD) independently assessed the eligibility of studies. Data were extracted systematically by the same reviewers, including details of patient characteristics, interventions and results. The methodological quality of all included studies was assessed using the quality assessment checklist adapted from the updated CONSORT guidelines.10 Disagreements were resolved by discussion.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Conflicts of interest
  9. References

The search returned 563 non-duplicate citations, from which seven eligible studies were identified (Figure 1). Two RCTs11,12 were excluded because they did not report body weight or composition as an outcome; another study was excluded because it was open-label.13 Thus, four RCTs14–17 with a total of 87 patients met the inclusion criteria and were included in the review. The key details of these RCTs are summarised in Tables 1 and 2.

image

Figure 1. Flow chart of study selection.

Download figure to PowerPoint

Table 1.  Methodological characteristics of included trials
First authorMain outcome(s)Main diagnoses of study participantsStudy designSex (M/F)Randomisation appropriate?Allocation concealed?Sample size determined?Groups similar at baseline?Outcome assessor blinded?Care provider blinded?Patients blinded?Attrition bias?ITT analysis?Modified lifestyle?
Year
Country
  1. Symbols: += yes; −= no; ? = unclear.

  2. BMI, body mass index; DB, double-blind; FFM, free fat mass; M/F: males/females; NR, not reported; REE, resting energy expenditure; WHR, waist-hip-ratio.

ArmstrongBody composition, REE, appetiteHealthy overweight/obese subjectsParallel, DB RCT3/10??++??+?+
200114
USA
ColkerBMI, body weight, FFM, WHRHealthy overweight adultsParallel, DB RCTNR???+??+?+
199915
USA
GreenwayBody weight, body fat, lean tissue, waist circumferenceHealthy overweight/obese subjectsParallel, DB RCT1/7???+????+
200616
USA
KalmanBody composition, mood, metabolic profileHealthy, active overweight/obese subjectsParallel, DB RCT3 2/7???+??+?+
200017
USA
Table 2.  Main results of included trials
First authorComposition of herbal supplementRandomised (n)Age in years (mean ± SD)Body weight (kg) at baseline (mean ± SD)Study durationMain resultsAdverse eventsAuthors' conclusion
Year
  • a

    Study had three groups of participants; analysis was confined to the Citrus aurantium and placebo groups.

  • BM, body mass; CA, C. aurantium; FM, fat mass; PLA, placebo.

ArmstrongSynephrine (5 mg), ephedrine (20 mg), caffeine (200 mg), salicin (15 mg), ginger root (50 mg), pantothenic acid (40 mg), thermosynergist blend (225 mg)2631 ± 6.6 for all subjects91.6 ± 16.1 (CA) 96.1 ± 19.2 (PLA)6 weeksA 2.57 kg loss in fat mass was observed in the experimental group compared with a 0.49 kg loss in the PLA group (P=0.033)Anxiety, elevated heart rate, feeling of ‘warmed blood’‘Supplement may result in reductions in FM, %fat and BM following 6 wks of supplementation and training’
200114
ColkeraSynephrine alkaloid (59 mg), Hypericin perforatum (St John's wort) (900 mg) caffeine (528 mg)23>21 for all subjects90.9 ± 17.5 (CA) 83.6 ± 17.5 (PLA)6 weeksA 1.4 kg loss in body weight was reported in the C. aurantium group compared with a 0.9 kg loss in the PLA group (P<0.05). Body fat reduced by 3.1 kg in the C. aurantium group (P=0.05), and increased by 0.8 kg in the PLA group (P>0.10)Not reportedC. aurantium extract when combined with caffeine and St. John's wort is effective in reducing body fat’
199915
GreenwaySynephrine (9 mg), green tea leaf extract (200 mg), caffeine (198 mg), salicin (7.5 mg), ginger root (10 mg), thermo-blend (375 mg), pantothenic acid (40 mg)839.5 ± 4.43 (CA) 44.5 ± 12.18 (PLA)76.4 ± 5.6 (CA) 70 ± 7.1 (PLA)8 weeksWeight gain was observed in both the herbal supplement (1.9%) and PLA (0.2%) groups (P<0.04)Headache, neurologic and musculoskeletal complaintsC. aurantium is not an effective dietary supplement for treatment of obesity’
200616
KalmanaSynephrine (5 mg), ephedrine alkaloids (20 mg), caffeine (200 mg), salicin (15 mg)3043.06 ± 9.9 (CA) 42.1 ± 10.5 (PLA)82.07 ± 14.4 (CA) 74.7 ± 14 (PLA)8 weeksA 3.14 kg weight loss was reported in the experimental group compared with a 2.05 kg loss in the PLA group (P=0.05). A 16% decrease in body fat was observed in the experimental group compared with a 1% decrease in the PLA group (P=0.005)Not reported‘Ephedrine-and synephrine based products are safe based on the confines of this study’
200017

All RCTs had considerable flaws in terms of methodological reporting (Table 1). No RCT reported appropriate randomisation or allocation concealment techniques, and no trial adequately reported blinding of care providers or outcome assessors. Three RCTs14,15,17 reported adequate blinding of study participants. One trial14 reported adequate sample size determination and no RCT included an ITT analysis. Two trials failed to mention adverse events; this is in breach of research ethics and guidelines for the reporting of clinical trials.10

All RCTs incorporated lifestyle modification into their trial regimen. Two RCTs15,16 reported daily caloric intakes ranging from 1200 kcal to 1800 kcal, while another17 prescribed a diet of 22 kcal/kg daily. One RCT14 did not report the daily caloric intakes of study participants. All trials incorporated exercise into the trial, with two RCTs15,17 using exercise physiologists to supervise study participants. Participants in one RCT16 were instructed to walk 30 min on most days of the week, while those in another trial14 performed aerobic exercises thrice weekly.

Three RCTs14,15,17 showed a marginal to statistically significant decrease in body weight in the herbal supplement group when compared with placebo (P≤0.05). The difference in weight loss between participants in the herbal supplement and placebo groups in each study was 1.67 kg, 0.5 kg and 1.09 kg, respectively (Table 2). Another RCT16 reported significant weight gain in the herbal supplement group when compared with placebo (P<0.04), with subjects in the herbal supplement group gaining 1.7% more weight than subjects in the placebo group.

Two RCTs14,17 reported a significant difference in fat loss between the herbal supplement group and placebo group. The between-group difference in fat loss reported in one of these RCTs14 was 2.09 kg (P=0.033), and in the other trial17 it was 15% (P<0.005). One RCT15 showed a fat loss of 3.1 kg in the herbal supplement group (P=0.05), while participants in the placebo group gained 0.8 kg (P>0.10). There was no mention of inter-group differences in this RCT. Another trial16 demonstrated fat gain in both the herbal supplement and placebo groups, with the herbal supplement group gaining about 0.3 kg more in fat than the placebo group. However, the difference between groups in fat gained was reported as not significant (no P-values reported).

There were variations in the dosages of C. aurantium extracts, as well as the composition of the dietary herbal supplements amongst the RCTs. Two trials reported synephrine doses of 10 mg,14,17 while another16 used a daily dose of 18 mg. Subjects in one RCT15 received a daily dose of SA totalling approximately 59 mg. All the trials included caffeine (or caffeine-derived products) in the herbal supplement, while two RCTs14,17 had Ephedra/ephedrine as part of the herbal supplement. Hypericum perforatum (St John's wort) was a component of the supplement in one trial,15 while salicin was a component of the supplement in three RCTs.14,16,17 Pantothenic acid was a part of the herbal supplement in two RCTs.14,16

All RCTs were of short duration, ranging from 6 to 7 weeks. Two RCTs14,15 monitored participant compliance with the diet regimen. While one of these14 analysed dietary compliance with statistical software, the other15 employed the use of telephone follow-up and dietary review sessions to assess compliance. Three trials15–17 reported the monitoring of participant compliance by counting the number of unused pills. While one of these RCTs16 reported an 80% compliance rate with the drug protocol, the other two trials15,17 did not report the compliance rates for drug intake.

Two RCTs14,16 mentioned adverse events, which included headache, anxiety, elevated heart rate, neurologic and musculoskeletal complaints. One trial17 reported synephrine-based products as being safe within the limits of the trial. In total, 14 dropouts occurred in three RCTs.14,15,17 One trial14 reported two dropouts for potential adverse events, without mentioning the specific symptoms. One RCT15 reported three dropouts without specifying the groups to which the subjects belonged. In two trials,15,17 the dropouts were unrelated to the treatment.

One RCT14 reported the brand name of the C. aurantium supplement (Xenadrine RFA-1), while the other trials did not.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Conflicts of interest
  9. References

We identified four RCTs investigating the use of C. aurantium-containing herbal supplements for weight reduction. While two of the RCTs15,17 reported significant reductions in weight among C. aurantium treated participants, a third trial14 found only marginal benefit for C. aurantium. The fourth RCT16 reported significant weight gain in the herbal supplement group when compared with placebo. Two RCTs14,17 reported significant reductions in body fat in the herbal supplement group when compared with placebo, whereas another RCT16 showed no significant difference in body fat between groups. A fourth trial15 reported positive effects of the herbal supplement on body fat, without providing the results of inter-group differences.

Both C. aurantium and SA have been postulated to cause weight reduction through a number of biological mechanisms. Animal studies have shown that p-synephrine (an SA) stimulates beta-adrenoreceptors, causing thermogenesis and lipolysis.18M-synephrine (phenylephrine), on the other hand, is thought to act as a sympathomimetic on alpha-1 adrenergic receptors.2,9 Another SA present in C. aurantium, octopamine, reportedly binds to alpha-adrenoreceptors15 to decrease cyclic adenosine monophosphate (cAMP) activity. This is thought to increase thermogenesis. Notwithstanding, the results of this systematic review do not indicate precisely how ingestion of C. aurantium and SA cause a reduction in body weight.

All RCTs included in this review had serious flaws in the reporting of their methodology, and they all had small sample sizes. The poor reporting of randomisation and blinding techniques in the RCTs casts major doubts on the internal and external validity of the studies. The small sample sizes of the trials also limit the applicability of the study results as small studies are prone to producing unreliable results.19 All RCTs were of short duration, which limits the conclusions that can be drawn from the long-term use of such herbal supplements.

All trials included in this review used supplements containing ingredients other than C. aurantium or SA, which have been demonstrated or suggested to have positive effects on body weight. The herbal supplement in two RCTs14,17 contained ephedrine, which has been demonstrated to be beneficial for weight management but is associated with an increased risk of serious adverse events.20 All the trials used supplements containing caffeine, which also might reduce body weight.20 Three RCTs14,16,17 contained salicin, which has been marketed as a weight-loss supplement without scientific evidential support. One RCT15 also contained H. perforatum (St John's wort), which has been marketed as a weight-loss supplement even though no RCTs have demonstrated any beneficial effect of the herb on body weight. The composition of the herbal supplements in all studies identified in this review creates uncertainty about the specific effects of C. aurantium and SA on body weight. To advance our knowledge, trials of single-ingredient products would be clearly preferable. The RCTs varied in the daily dosage of the supplement, and thus the optimal dose (if any exists) remains unknown.

There is some uncertainty regarding the safety of C. aurantium. Although two RCTs reported adverse events associated with the consumption of the herbal supplement, it may be erroneous to conclude that the adverse events were entirely due to the C. aurantium component of the supplement. Furthermore, a recent review of the safety of C. aurantium concluded that bitter orange extracts and p-synephrine appear to be safe.18 It would be prudent for future investigators to incorporate surveillance time-frames into their trials to assess specific C.aurantium-associated adverse events in this regard.

There is still some controversy about the active ingredients in C. aurantium. While some authors state that C. aurantium contains both synephrine and phenylephrine,2 other authors have reported that phenylephrine is not a component of C. aurantium.3,18 This issue warrants further investigation and clarification.

All the RCTs identified in this review disclosed their source of funding and, to date, all have been funded by industry. Thus, more independent trials are required; these trials also should be of larger size and of longer duration.

This review has several limitations. Though a robust search strategy was employed, not all available RCTs involving the use of herbal supplements containing C. aurantium or SA may have been identified. The composition of the herbal supplements used in the included studies also limits the conclusions that can be drawn about the effects of this supplement on human body composition.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Conflicts of interest
  9. References

The evidence from RCTs regarding the effects of C. aurantium and SA on body weight are contradictory, and the studies examined are methodologically weak. Future studies in this area should avoid the methodological flaws of the RCTs reviewed here.

Conflicts of interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Conflicts of interest
  9. References

IO has a research fellowship with GlaxoSmithKline. The funder had no role in the preparation of this manuscript. LD and EE have no conflicts of interest to declare.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Conflicts of interest
  9. References

Igho Onakpoya, MD, MSc, Complementary Medicine Research Group, Peninsula Medical School, Universities of Exeter and Plymouth, Veysey Building, Salmon Pool Lane, Exeter EX2 4SG, UK.

Lucy Davies, PhD, Complementary Medicine Research Group, Peninsula Medical School, Universities of Exeter and Plymouth, Veysey Building, Salmon Pool Lane, Exeter EX2 4SG, UK.

Edzard Ernst, MD, PhD, FMedSci, FSB, FRCP, FRCPEd, Editor-in-Chief of FACT, Laing Chair in Complementary Medicine, Peninsula Medical School, Universities of Exeter and Plymouth, Veysey Building, Salmon Pool Lane, Exeter EX2 4SG, UK.