4 Advice to Choose a Citrus Aurantium Extract Powder

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Associated Data

Supplementary Materials

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Data Availability Statement

The data presented in this study are available in this article and in the Supplementary Material.

Abstract

Synephrine has been used to promote weight loss; however, its safety and efficacy have not been fully established. The goals of our study were to give an overview of the safety and efficacy of p-synephrine, to systematically evaluate its efficacy regarding weight loss and to assess its safety, focusing on its cardiovascular side effects in a meta-analysis. PubMed, the Cochrane Library, Web of Science and Embase were searched for relevant studies. Only placebo-controlled, human clinical trials with synephrine intervention were included in the meta-analysis. The meta-analysis was reported according to the PRISMA guidelines using the PICOS format and taking into account the CONSORT recommendations. Altogether, 18 articles were included in the meta-analysis. Both systolic and diastolic blood pressure (DBP) increased significantly after prolonged use (6.37 mmHg, 95% CI: 1.02&#;11.72, p = 0.02 and 4.33 mmHg, 95% CI: 0.48&#;8.18, p = 0.03, respectively). The weight loss in the synephrine group was non-significant after prolonged treatment, and it did not influence body composition parameters. Based on the analyzed clinical studies, synephrine tends to raise blood pressure and heart rate, and there is no evidence that synephrine can facilitate weight loss. Further studies are needed to confirm evidence of its safety and efficacy.

Keywords:

p-synephrine, meta-analysis, obesity, food supplements, weight loss

1. Introduction

The global increase in obesity is strongly connected to modifiable lifestyle factors, including sedentary lifestyle and diet [1]. Obesity is associated with serious health problems and related comorbidities [2,3], and even modest weight loss can result in improved systolic and diastolic blood pressure and blood cholesterol levels [4]. Increased physical activity, a low-calorie diet and the monitoring of body weight can facilitate weight loss in the long term [5].

Dietary supplements are easily available alternatives to medicines; however, data supporting their efficacy are usually scarce, and in some cases, their safety is also questionable [6]. Because of safety concerns, several Active Pharmaceutical Ingredients (APIs), that were considered as effective compounds to support weight loss are no longer available on the market. p-Synephrine, a protoalkaloid extracted from the immature fruit or peel of bitter orange (Citrus × aurantium L.), is widely used in weight loss and sports performance products [7], yet its efficacy and safety has not been fully established [8].

Synephrine exists in three different positional isomeric forms (ortho, meta and para) [9] ( ). It is generally accepted that only para-synephrine (p-synephrine) can be found in bitter orange fruits [10,11,12]. Food supplements can contain meta (m)- and p-synephrine, which are both alpha-adrenergic agonists (α-agonists), while the m-isoform is the most potent on alpha-1-adrenoreceptors (α1-adrenergic receptors) [13]. Ortho-synephrine (o-synephrine) is not used as a pharmaceutical substance, and its natural occurrence has not been documented [13,14]. Methyl-synephrine HCl (4-HMP, syn. oxilofrine HCl) is a prohibited synthetic derivative of p-synephrine and has been reported as an adulterant in food supplements [15,16,17,18].

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Since the use of ephedrine in food supplements has become prohibited in several European countries and in the USA, p-synephrine has gained considerable interest as the main substitute of ephedrine in weight loss products [12,19,20,21]. Synephrine is similar to ephedrine with regard to its structure and mechanism of action; however, it is less lipophilic, resulting in decreased transport through the blood&#;brain barrier [7,22,23,24]. The use of ephedrine is associated with the increased risk of myocardial infarction, hypertension, and stroke [12,25], but such pronounced effects on the cardiovascular system are not expected when using p-synephrine. Animal studies have shown that p-synephrine stimulates beta-adrenoreceptors, causing thermogenesis and lipolysis [7], whereas its cardiovascular adverse effects are partly due to its α-adrenergic receptor affinity [26]. Although it is generally acknowledged that p-synephrine has milder side effects than ephedrine, its safety and efficacy have not yet been thoroughly studied [8,19].

p-Synephrine (hereinafter referred to as synephrine) is used in pre-workout supplements to improve performance and to promote weight loss since it has thermogenic and sympathomimetic properties [27,28]. Synephrine was added to the Monitoring Program in Competitions of the World Anti-Doping Agency [29], but it is not yet considered as a prohibited substance (WADA) in [30]. However, it is prohibited for use by several professional sporting agencies (the National Collegiate Athletic Association (NCAA), Major League Baseball (MLB), and the National Football League (NFL)) [31].

Currently, there is little if any basis for making definitive statements about the safety of bitter orange extracts or synephrine used in food supplements [9]. Cardiac adverse events, including hypertension, tachyarrhythmia, variant angina, cardiac arrest, QT prolongation, ventricular fibrillation, myocardial infarction, and sudden death, have been the most common adverse effects associated with synephrine intake [27]; however, the prevalence is not known. The average synephrine content of the dried fruit extracts of Citrus aurantium has been reported to be between 3% and 6% [9,10,32,33,34]. The French food safety authority (ANSES) concluded in its assessment on synephrine [35] that the intake levels of synephrine from food supplements must remain below 20 mg/day, and it is not recommended to take synephrine in combination with caffeine. It is also recommended to avoid the use of products containing synephrine during physical exercise, and its use by sensitive individuals is discouraged (i.e., people taking certain medications, pregnant or breastfeeding women, children, and adolescents) [35,36]. Because of its known sympathomimetic properties and adrenergic effects on the cardiovascular system, the use of synephrine in food supplements is debated [36]. Even though there is no legislation which limits the content of synephrine and other alkaloids in dietary supplements, based on the Directive /46/EC, each country is supposed to set a maximum level of synephrine [37,38]. There have been reports in the RASFF (Rapid Alert System for Food and Feed) about synephrine, because in some countries, there is a limit regarding its daily dose, and in the reported cases, the products contained more than the maximum [39] (Table S1, Figure S1).

2. Materials and Methods

2.1. Literature Search and Selection Criteria

Electronic searches were conducted in the following databases: PubMed, Embase, Web of Science (WoS), and the Cochrane Library. Each database was searched until 17 August . The searching method included the key term synephrine. This meta-analysis of eligible peer reviewed studies was reported in accordance with the PRISMA statement and followed the CONSORT recommendations. Trials were selected if they were (1) human clinical studies, (2) compared known doses of orally used synephrine with a placebo or active control or both, and (3) completed. In order to complete this task, the following PICO (patients, intervention, comparison, outcome) format was applied: P: adults; I: known dosage of p-synephrine given per os; C: placebo or control; and O: changes in the body weight, composition, cardiovascular, and metabolic parameters (i.e., heart rate, blood pressure, body weight, body fat, fat mass, fat-free mass, fasting blood sugar level, and RER values). Our hypothesis was that synephrine facilitates weight loss and that its use correlated with cardiovascular adverse effects. This work was registered in PROSPERO (). There were no restrictions regarding the number of included patients or the minimal or maximal dosing of p-synephrine. The language of the included articles was restricted to English.

2.2. Data Extraction and Endpoints

As clarified in the PICO, clinical trials involving adults were included in this meta-analysis. Of these clinical trials, outcomes related to the efficacy and safety of synephrine were extracted. The study endpoints included those values which were present in at least three articles and could be compared. Statistical evaluation could modify the finally analyzed trials/outcomes. The following information from individual studies was extracted: the first author&#;s name and publication year; the study design and population; the number of participants; other medicines in the intervention group; synephrine regimen; and outcomes.

2.3. Quality Evaluations

Two authors (D.K. and D.CS.) performed the literature search. Both authors reviewed the full-text articles and extracted appropriate data from the publications. The risk of bias was analyzed by two of the authors (D.CS. and B.T.), using the Cochrane Risk of Bias Tool, which includes the following domains: random sequence generation, allocation concealment, the blinding of participants and personnel, the blinding of outcome assessment, incomplete outcome data, selective reporting and other scores of bias. For each domain, studies were judged to have a high (red), unclear (yellow), or low (green) risk of bias (Figure S2 and S3). Disagreements were resolved by consensus. Risk of bias figures were prepared by using the Review Manager (RevMan) version 5.4.1 software from Cochrane Training site based in London, UK.

2.4. Statistical Analysis

An outcome was selected for the final analysis if it was reported in at least three articles; however, further attrition and unique time intervals could modify the analyzed study number/outcome. The assessment of weighted mean difference (MD) and effect sizes (ESs) between test and control group values (synephrine vs. control) was performed as a post&#;post analysis. A Chi2 or Tau2 test was used to evaluate the heterogeneity. Deviating study intervention arms were excluded from the final analysis in case there were other extra intervention(s) apart from synephrine (mainly caffeine). In the case of heterogenous subjects based on their caffeine usage, the regular non-caffeine users were selected contrasting to regular high caffeine users. The statistical analyses were conducted using the Review Manager 5.4.1 software. The results were considered statistically significant when the p value was less than 0.05.

4. Discussion

Overall, 18 trials involving 341 adults were analyzed to perform this meta-analysis. Different sets depending on each outcome were applied to assess the weight loss effects of synephrine and to establish its safety based on its effects on cardiovascular variables. Based on the literature, the commonly used doses of p-synephrine vary from 25 to 100&#;mg per day [16,60,61], while our analysis included 6&#;214 mg of synephrine. Based on our meta-analysis, synephrine did not significantly increase systolic blood pressure acutely, but it significantly increased in the long term (p = 0.02) ( ). It had less significant acute effects on diastolic blood pressure and showed similarly significant effects when applied for longer durations (8 weeks) (p = 0.03) ( ). After the acute administration of synephrine, the heart rate increased, but the change remained non-significant; the highest increase was measured 3 h after consumption (p = 0.07) ( ). Our analysis led to the conclusion that the prolonged use of synephrine did not result in significant alterations in body weight and composition ( ). Based on the analyzed data, the acute administration of synephrine did not change blood glucose and RER values ( and Figure S5).

Synephrine&#;s impacts on cardiovascular health can be predicted by looking at its effects on cardiovascular variables. Since the use of ephedrine is associated with the increased risk of cardiovascular morbidity and mortality, a similarly effective but safe alternative would be greatly appreciated [9,62]. The dosage used during weight loss analysis was 10&#;54 mg daily for 42&#;56 days, which nearly coincides with the dosage that resulted in cardiovascular adverse events (increased blood pressure) after 56&#;60 days after the administration of 10&#;49 mg of synephrine. Based on our results, the use of synephrine does not lack cardiovascular side effects; therefore, it may not be a safe alternative to ephedrine for those with predisposing comorbidities.

p-Synephrine-containing products are marketed for those aiming for higher energy utilization during low- to moderate-intensity exercise [8]. However, it is not yet proven that bitter orange or synephrine consumption can reduce body fat or promote weight loss [8]. Based on our meta-analysis, the prolonged use of synephrine does not result in significant weight loss (p = 0.85). A mean difference of 0.6 kg was observed in a total of 94 subjects (47 subjects/intervention with a daily dose of 10&#;54 mg of synephrine). Synephrine was ineffective in influencing body fat (&#;1.87%, n = 94, p = 0.07), fat mass (&#;0.32 kg, n = 69, p = 0.85), and fat-free mass (&#;0.47 kg, n = 78, p = 0.84).

Some results suggest that p-synephrine has the potential to maintain blood glucose levels by stimulating the uptake of excess blood glucose via insulin-dependent or -independent mechanisms in skeletal muscles [63]. Maintaining optimal blood glucose values would be beneficial, suggesting greater hepatic glucose release, which would be favorable during exercise [45,64]. Based on our results, consuming synephrine did not alter blood glucose levels significantly (p = 0.24), and blood glucose maintenance was not affected by the consumption of 6&#;103 mg of synephrine.

Higher RER values indicate that carbohydrates are being predominantly used as fuel, and lower RER values suggest lipid oxidation [65,66]. Physically active and trained subjects exhibit lower RER values than untrained sedentary subjects in response to comparable workloads [67,68,69]. Our analysis included three articles with 33 analyzed subjects overall. In these trials, the effects of synephrine were assessed after 1 h of consumption. After 2&#;3 h of consumption, data from only 20 subjects were available. Our results suggest that the consumption of 6-103 mg of synephrine does not modify RER values significantly. RER value changes in the studies were presumably related to caffeine, and all three of the analyzed trials administered a supplement which had additional caffeine in it [47].

The strengths of this systematic review with meta-analysis are that only data from published peer-reviewed articles were used, and all the included trials were double-blind trials. However, there are several limitations to the analysis. First, the studied products were different and contained varying doses (6&#;214 mg) of synephrine with different isometric forms. One study included both m- and p-synephrine [46], and one study examined the effects of methyl-synephrine HCl [44]. Only six studies included isolated p-synephrine [53,54,55,56,57,59]. In the remaining ten studies, the applied products (such as bitter orange extract) contained standardized synephrine [43,48,49] or were mixed with other substances [22,44,45,47,50,52,58]. The main limitation of the study was high attrition, and only a few studies assessed the same outcomes, resulting in relatively small plots. There were no mentions of the the subjects&#; ethnicities, which weakens the results, as it is not clear if the groups were diverse enough in this regard. On the other hand, subjects showed a high variety of traits regarding physical activity and age, and more males were analyzed. Some trials included an exercise intervention, which made the data more heterogonous. Previously, Stohs et al. performed a detailed systematic review of synephrine, but there was no meta-analysis on this topic with statistical evaluations; only a literature review was performed [70]. The only available meta-analysis examined oral phenylephrine on nasal airway resistance in patients with nasal congestion, which did not examine p-synephrine and did not analyze its weight loss effects [71].

5. Conclusions

After the ban of Ephedra sinica by the FDA in , there was a clear need for an alternative weight loss supplement with favorable safety profile [12,25]. Synephrine was widely used to promote weight loss, and it is often considered as a safe and effective option, but its safety and efficacy is yet to be studied. When applying synephrine, it should be taken into account that it also has sympathomimetic effects, so it may also increase systolic blood pressure, diastolic blood pressure, and heart rate. Consequently, it may also increase the risk for stroke and myocardial infarction and therefore harm the consumers&#; health. Hence, the hemodynamic effects of bitter orange and p-synephrine must be established, but unfortunately, studies related to synephrine-induced cardiotoxicity are scarce [27,43].

p-Synephrine showed a tendency to increase systolic blood pressure and heart rate acutely, and it significantly increased both systolic and diastolic blood pressure when applied for longer durations. Therefore, our meta-analysis revealed safety concerns related to the use of synephrine. The beneficial effects of synephrine were rather inconclusive. In our meta-analysis, it did not promote weight loss, and neither did it cause beneficial effects on body composition. The overall effects on glucose and RER values were not proved to be favorable. The currently available evidence indicates that synephrine influences blood pressure and heart rate but has no significant effects on weight loss and body composition; therefore, its use is not recommended to promote health. Considering the limitations, it is concluded that further and larger trials are needed to assess the efficacy and safety of synephrine with a lower risk of bias.

Abbreviations

ANSESThe French Agency for Food, Environmental and Occupational Health & SafetyBPBlood pressureCA Citrus aurantium CIConfidence intervalDBPDiastolic blood pressureHCLHydrochlorideHRHeart rateEEpinephrineECEuropean CommissionEEEnergy expenditureEUEuropean UnionFDAU.S. Food and Drug AdministrationMDMean differenceNANoradrenalineNENorepinephrineNKNot knownmmHgMillimeters of mercurym-synephrineMeta-synephrine (phenylephrine)p-synephrinePara-synephrineQTMeasurement made on electrocardiogram. It is calculated as the time from the start of the Q wave to the end of the T wave.RASFFRapid Alert System for Food and FeedRCTRandomized clinical trialRERRespiratory exchange ratioSBPSystolic blood pressureSDStandard deviationVO2Oxygen consumption4-HMPMethyl-synephrine HCl, oxiflorine

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10./nu/s1, Table S1: Unauthorized synephrine (above maximal limit) products in the European Union in the RASFF system from to ; Table S2: Characteristics of the trials; Table S3: Demography of patients; Figure S1. Unauthorized synephrine (above maximal limit) products in the RASFF system from to (accessed on 31 December ).; Figure S2: Risk of bias graph on synephrine meta-analysis; Figure S3: Risk of bias summary on synephrine meta-analysis; Figure S4: Forest plot diagram of synephrine on (h/2) blood glucose for short duration in intervention and control groups with one change in the time duration; Figure S5: Forest plot diagram of synephrine on (i) RER values after 1&#;3 h (1 h two times with one change in time interval) in intervention and control groups.

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Funding Statement

Project No. TKP-EGA-32 has been implemented with the support provided by the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund, financed under the TKP-EGA funding scheme.

Author Contributions

Conceptualization, D.K. and D.C.; methodology, D.C.; software, M.A.B. and B.T.; formal analysis, D.K.; investigation, D.K. and D.C.; data curation, B.T., D.C. and M.A.B.; writing&#;original draft preparation, D.K.; writing&#;review and editing, D.C., O.R. and B.T.; visualization, B.T., M.A.B. and D.K.; supervision, O.R. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in this article and in the Supplementary Material.

Conflicts of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Footnotes

Publisher&#;s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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