Citrus p-Synephrine Improves Energy Homeostasis by Regulating Amino Acid Metabolism in HFD-Induced Mice.

p-Synephrine is a common alkaloid widely distributed in citrus fruits. However, the effects of p-synephrine on the metabolic profiles of individuals with energy abnormalities are still unclear. In the study, we investigated the effect of p-synephrine on energy homeostasis and metabolic profiles using a high fat diet (HFD)-induced mouse model. We found that p-synephrine inhibited the gain in body weight, liver weight and white adipose tissues weight induced by HFD. p-Synephrine supplementation also reduced levels of serum total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) but not to a statistically significant degree. Histological analysis showed that HFD induced excessive lipid accumulation and glycogen loss in the liver and adipocyte enlargement in perirenal fat tissue, while p-synephrine supplementation reversed the changes induced by HFD. Moreover, HFD feeding significantly increased mRNA expression levels of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) and reduced the mRNA expression level of interleukin-10 (IL-10) compared to the control group, while p-synephrine supplementation significantly reversed these HFD-induced changes. Liver and serum metabolomic analysis showed that p-synephrine supplementation significantly altered small molecule metabolites in liver and serum in HFD mice and that the changes were closely associated with improvement of energy homeostasis. Notably, amino acid metabolism pathways, both in liver and serum samples, were significantly enriched. Our study suggests that p-synephrine improves energy homeostasis probably by regulating amino acid metabolism in HFD mice, which provides a novel insight into the action mechanism of p-synephrine modulating energy homeostasis.

Stachydrine, a Bioactive Equilibrist for Synephrine, Identified from Four Citrus Chinese Herbs.

Four Chinese herbs from the Citrus genus, namely Aurantii Fructus Immaturus (Zhishi), Aurantii Fructus (Zhiqiao), Citri Reticulatae Pericarpium Viride (Qingpi) and Citri Reticulatae Pericarpium (Chenpi), are widely used for treating various cardiovascular and gastrointestinal diseases. Many ingredients have already been identified from these herbs, and their various bioactivities provide some interpretations for the pharmacological functions of these herbs. However, the complex functions of these herbs imply undisclosed cholinergic activity. To discover some ingredients with cholinergic activity and further clarify possible reasons for the complex pharmacological functions presented by these herbs, depending on the extended structure-activity relationships of cholinergic and anti-cholinergic agents, a simple method was established here for quickly discovering possible choline analogs using a specific TLC method, and then stachydrine and choline were first identified from these Citrus herb decoctions based on their NMR and HRMS data. After this, two TLC scanning (TLCS) methods were first established for the quantitative analyses of stachydrine and choline, and the contents of the two ingredients and synephrine in 39 samples were determined using the valid TLCS and HPLC methods, respectively. The results showed that the contents of stachydrine (3.04‱) were 2.4 times greater than those of synephrine (1.25‱) in Zhiqiao and about one-third to two-thirds of those of Zhishi, Qingpi and Chenpi. Simultaneously, the contents of stachydrine, choline and synephrine in these herbs present similar decreasing trends with the delay of harvest time; e.g., those of stachydrine decrease from 5.16‱ (Zhishi) to 3.04‱ (Zhike) and from 1.98‱ (Qingpi) to 1.68‱ (Chenpi). Differently, the contents of synephrine decrease the fastest, while those of stachydrine decrease the slowest. Based on these results, compared with the pharmacological activities and pharmacokinetics reported for stachydrine and synephrine, it is indicated that stachydrine can be considered as a bioactive equilibrist for synephrine, especially in the cardio-cerebrovascular protection from these citrus herbs. Additionally, the results confirmed that stachydrine plays an important role in the pharmacological functions of these citrus herbs, especially in dual-directionally regulating the uterus, and in various beneficial effects on the cardio-cerebrovascular system, kidneys and liver.

Effect of p-Synephrine on Fat Oxidation Rate during Exercise of Increasing Intensity in Healthy Active Women.

p-Synephrine is the principal alkaloid of bitter orange (Citrus aurantium). Several recent investigations have found that the intake of 2-3 mg/kg of p-synephrine raises fat oxidation rate during exercise of low-to-moderate intensity. However, these investigations have been carried out only with samples of male participants or mixed men/women samples. Therefore, the aim of this investigation was to study the effect of p-synephrine intake on fat oxidation during exercise of increasing intensity in healthy women. Using a double-blind, randomized experiment, 18 healthy recreationally active women performed two identical exercise trials after the ingestion of (a) 3 mg/kg of p-synephrine and (b) 3 mg/kg of a placebo (cellulose). The exercise trials consisted of a ramp test (from 30 to 80% of maximal oxygen uptake; VO2max) on a cycle ergometer while substrate oxidation rates were measured at each workload by indirect calorimetry. In comparison to the placebo, the intake of p-synephrine increased resting tympanic temperature (36.1 ± 0.5 vs. 36.4 ± 0.4 °C p = 0.033, d = 0.87) with no effect on resting heart rate (p = 0.111) and systolic (p = 0.994) and diastolic blood pressure (p = 0.751). During exercise, there was no significant effect of p-synephrine on fat oxidation rate (F = 0.517; p = 0.484), carbohydrate oxidation rate (F = 0.730; p = 0.795), energy expenditure rate (F = 0.480; p = 0.833), heart rate (F = 4.269; p = 0.068) and participant's perceived exertion (F = 0.337; p = 0.580). The maximal rate of fat oxidation with placebo was 0.26 ± 0.10 g/min and it was similar with p-synephrine (0.28 ± 0.08 g/min, p = 0.449, d = 0.21). An acute intake of 3 mg/kg of p-synephrine before exercise did not modify energy expenditure and substrate oxidation during submaximal aerobic exercise in healthy active women. It is likely that the increase in resting tympanic temperature induced by p-synephrine hindered the effect of this substance on fat utilization during exercise in healthy active women.

The Safety and Efficacy of Citrus aurantium (Bitter Orange) Extracts and p-Synephrine: A Systematic Review and Meta-Analysis.

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.

Synephrine and caffeine combination promotes cytotoxicity, DNA damage and transcriptional modulation of apoptosis-related genes in human HepG2 cells.

The abusive consumption of thermogenic supplements occurs worldwide and deserves special attention due to their use to stimulate weight loss and prevent obesity. Thermogenic formulations usually contain Synephrine (SN) and Caffeine (CAF), stimulating compounds extracted from natural sources, but no genetic toxicology studies have predicted this hazardous combination potential. This study examined the toxicogenomic responses induced by SN and CAF, either alone or in combination, in the human hepatic cell line HepG2 in vitro. SN (0.03-30 µM) and CAF (0.6-600 µM) alone did neither decrease cell viability nor induce DNA damage, as assessed using the MTT and comet assays, respectively. SN (3 µM) and CAF (30-600 µM) were combined at concentrations similar to those found in commercial dietary supplements. SN/CAF at 3:90 and 3:600 µM ratios significantly decreased cell viability and increased DNA damage levels in HepG2 cells. CAF (600 µM) and the SN/CAF association at 3:60, 3:90, and 3:600 µM ratios promoted cell death by apoptosis, as demonstrated by flow cytometry. Similar results were observed in gene expression (RT-qPCR): SN/CAF up-regulated the expression of apoptosis- (BCL-2 and CASP9) and DNA repair-related (XPC) genes. SN/CAF at 3:90 µM also downregulated the expression of cell cycle control (CDKN1A) genes. In conclusion, the SN/CAF combination reduces cell viability by inducing apoptosis, damages DNA, and modulates the transcriptional expression of apoptosis-, cell cycle-, and DNA repair-related genes in human hepatic (HepG2) cells in vitro. These effects can be worrisome to consumers of thermogenic supplements.

Deciphering the synergistic network regulation of active components from SiNiSan against irritable bowel syndrome via a comprehensive strategy: Combined effects of synephrine, paeoniflorin and naringin.

BACKGROUND: SiNiSan (SNS) is an ancient Chinese herbal prescription, and the current clinical treatment of irritable bowel syndrome (IBS) is effective. In the previous study of the research team, the multi-functional co-synergism of SNS against IBS was presented. Some potential drug targets and candidate ligands were predicted. PURPOSE: This study attempts to explore the crucial ingredient combinations from SNS formula and reveal their synergistic mechanism for IBS therapy. MATERIALS AND METHODS: In present study, a comprehensive strategy was performed to reveal IBS related pathways and biological modules, and explore synergistic effects of the ingredients, including ADME (absorption, distribution, metabolism, excretion) screening, Text mining, Venn analysis, Gene ontology (GO) analysis, Pathway cluster analysis, Molecular docking, Network construction and Experimental verification in visceral hypersensitivity (VHS) rats. RESULTS: Three compressed IBS signal pathways were derived from ClueGO KEGG analysis of 63 IBS genes, including Neuroactive ligand-receptor interaction, Inflammatory mediator regulation of TRP (transient receptor potential) channels and Serotonergic synapse. A multi-module network, composed of four IBS therapeutic modules (psychological, inflammation, neuroendocrine and cross-talk modules), was revealed by Target-Pathway network. Nine kernel targets were considered closely associated with the IBS pathways, including ADRA2A, HTR2A, F2RL1, F2RL3, TRPV1, PKC, PKA, IL-1Β and NGF. In silico analysis revealed that three crucial ingredients (synephrine, paeoniflorin and naringin) were assumed to coordinate the network of those IBS therapeutic modules by acting on these kernel targets in the important pathways. In vivo experimental results showed that the crucial ingredient combinations synergistically affected the expressions of the kernel biological molecules, and improved the minimum capacity threshold of AWR in VHS rats. CONCLUSION: The study proposes the important IBS associated pathways and the network regulation mechanisms of the crucial ingredients. It reveals the multi-target synergistic effect of the crucial ingredient combinations for the novel therapy on IBS.

Effects of p-Synephrine during Exercise: A Brief Narrative Review.

The p-synephrine is the principal phytochemical found in bitter orange (Citrus aurantium). This substance is widely included in dietary supplements for weight loss/body fat reduction due to its potential benefits of increasing fat oxidation. For years, p-synephrine-containing dietary supplements have been marketed without proper knowledge of their true effectiveness to enhance fat utilization, especially when combined with exercise. However, the effects of p-synephrine on fat oxidation during exercise have been investigated in the last few years. The aim of the current discussion is to summarize the evidence on the effects of p-synephrine intake on fat oxidation and performance during exercise. Previous investigations have demonstrated that the acute intake of p-synephrine does not modify running sprint performance, jumping capacity, or aerobic capacity. However, the acute intake of p-synephrine, in a dose of 2-3 mg/kg of body mass, has been effective to enhance the rate of fat oxidation during incremental and continuous exercise. This effect has been observed in a range of exercise workloads between 30% and 80% of peak oxygen uptake (VO2peak). The p-synephrine has the ability to increase the maximal rate of fat oxidation during exercise of increasing intensity without affecting the workload at which maximal fat oxidation is obtained (Fatmax). The effect of p-synephrine on fat oxidation is normally accompanied by a concomitant reduction of carbohydrate utilization during exercise, without modifying the energy expended during exercise. The shifting in substrate oxidation is obtained without any effect on heart rate during exercise and the prevalence of adverse effects is negligible. Thus, the acute use of p-synephrine, or p-synephrine-containing products, might offer some benefits for those individuals seeking higher fat utilization during exercise at low to moderate intensities. However, more research is still necessary to determine if the effect of p-synephrine on fat oxidation during exercise is maintained with chronic ingestion, in order to ascertain the utility of this substance in conjunction with exercise programs to produce an effective body fat/weight loss reduction.

p-Synephrine, ephedrine, p-octopamine and m-synephrine: Comparative mechanistic, physiological and pharmacological properties.

Confusion and misunderstanding exist regarding the lack of cardiovascular and other adverse health effects of p-synephrine and p-octopamine relative to ephedrine and m-synephrine (phenylephrine) which are known for their effects on the cardiovascular system. These four molecules have some structural similarities. However, the structural and stereochemical differences of p-synephrine and p-octopamine as related to ephedrine and m-synephrine result in markedly different adrenergic receptor binding characteristics as well as other mechanistic differences which are reviewed. p-Synephrine and p-octopamine exhibit little binding to α-1, α-2, ß-1 and ß-2 adrenergic receptors, nor are they known to exhibit indirect actions leading to an increase in available levels of endogenous norepinephrine and epinephrine at commonly used doses. The relative absence of these mechanistic actions provides an explanation for their lack of production of cardiovascular effects at commonly used oral doses as compared to ephedrine and m-synephrine. As a consequence, the effects of ephedrine and m-synephrine cannot be directly extrapolated to p-synephrine and p-octopamine which exhibit significantly different pharmacokinetic, and physiological/pharmacological properties. These conclusions are supported by human, animal and in vitro studies that are discussed.

Acute p-synephrine ingestion increases whole-body fat oxidation during 1-h of cycling at Fatmax.

PURPOSE: p-Synephrine, the principal alkaloid of bitter orange (Citrus aurantium), is widely used in dietary supplements for weight loss due to its purported effect of increasing fat oxidation. However, there is a paucity of scientific information about its effectiveness in enhancing fat oxidation during exercise. The aim of this investigation was to determine the effect of an acute dose of p-synephrine on substrate oxidation during prolonged and constant intensity exercise. METHODS: In a double-blind and randomized experiment, 14 healthy subjects performed two acute experimental trials after ingesting either p-synephrine (3 mg kg-1) or a placebo (cellulose). Energy expenditure and fat oxidation rates were continuously measured by indirect calorimetry during 1 h of continuous cycling at Fatmax, the intensity that induces maximal fat oxidation rate. RESULTS: In comparison to the placebo, energy expenditure during 1 h of cycling remained unchanged with p-synephrine (698 ± 129 vs. 686 ± 123 kcal, P = 0.08). However, p-synephrine increased whole-body fat oxidation (33.6 ± 10.4 vs. 37.3 ± 9.8 g, P < 0.01) while also reducing carbohydrate oxidation (99.5 ± 30.4 vs. 85.0 ± 28.4 g, P < 0.01). However, the magnitude of the shift on substrate oxidation induced by p-synephrine was small. CONCLUSION: Acute ingestion of p-synephrine augments fat oxidation during prolonged and constant-intensity exercise.

Differential mechanisms of action of the trace amines octopamine, synephrine and tyramine on the porcine coronary and mesenteric artery.

Trace amines such as p-tyramine, p-octopamine and p-synephrine are found in low concentrations in animals and plants. Consumption of pre-workout supplements containing these plant-derived amines has been associated with cardiovascular side effects. The aim of this study was to determine the mechanisms of action of these trace amines on porcine isolated coronary and mesenteric arteries. Noradrenaline caused contraction of mesenteric arteries and relaxation of coronary arteries. In both tissues, all three trace amines induced contractions with similar potencies and responses were unaffected by the ß-adrenoceptor antagonist propranolol (1 µM), the nitric oxide synthase inhibitor L-NNA (100 µM), or the TAAR-1 antagonist, EPPTB (100 nM). However, the contractile responses of mesenteric arteries, but not coronary arteries, were significantly reduced by depletion of endogenous noradrenaline. Mesenteric responses to all three amines were abolished in the presence of prazosin (1 µM) whereas residual contractile responses remained in the coronary artery which were inhibited by a high concentration (100 µM) of EPPTB. The results suggest complex responses of the coronary artery to the trace amines, with activity at α1-adrenoceptors and potentially TAARs other than TAAR-1. In contrast the actions of the amines on the mesenteric artery appeared to involve indirect sympathomimetic actions and direct actions on α1-adrenoceptors.

Co-Existence of Hypertensive and Anti-Hypertensive Constituents, Synephrine, and Nobiletin in Citrus unshiu Peel.

A single herb can contain multiple constituents with diverse bioactivities. We found that the extract of Citrus unshiu peel (CUP), induced abnormal vasoconstriction responses on the freshly isolated rat aortic rings in vitro. CUP stimulated the vasoconstriction alone, and it suppressed the phenylephrine-stimulated vasoconstriction. We studied the reasons behind this abnormal vasoconstriction pattern. Major constituents of CUP were determined and evaluated for their vaso-activities. Notably, synephrine, a contractile agonist, and nobiletin, newly identified to have anti-contractile activity co-existed in CUP. Synephrine and nobiletin competitively blocked or activated the same contractile targets resulting in contradicting and abnormal vasoconstriction responses. Accordingly, the vasoconstriction pattern varies significantly depending on the relative contents of synephrine and nobiletin in CUP. Interestingly, this response pattern could be observed with another plant extract, Acorus gramineus Sol. Collectively, we demonstrated that active ingredients with contradicting bioactivities could co-exist in a single plant extract, interact and produce abnormal response patterns in bioassay, which would give an important insight into the interpretation of unusual activity patterns induced by plant extracts.

An Overview on Citrus aurantium L.: Its Functions as Food Ingredient and Therapeutic Agent.

Citrus aurantium L. (Rutaceae), commonly known as bitter orange, possesses multiple therapeutic potentials. These biological credentials include anticancer, antianxiety, antiobesity, antibacterial, antioxidant, pesticidal, and antidiabetic activities. The essential oil of C. aurantium was reported to display marked pharmacological effects and great variation in chemical composition depending on growing locations but mostly contained limonene, linalool, and ß-myrcene. Phytochemically, C. aurantium is rich in p-synephrine, an alkaloid, and many health-giving secondary metabolites such as flavonoids. Animal studies have demonstrated a low affinity of p-synephrine for adrenergic receptors and an even lower affinity in human models. The present review focuses on the different biological activities of the C. aurantium in animal and human models in the form of extract and its pure secondary metabolites. Finally, it is concluded that both the extract and isolated compounds have no unwanted effects in human at therapeutic doses and, therefore, can confidently be used in various dietary formulations.

Effects of p-Synephrine and Caffeine Ingestion on Substrate Oxidation during Exercise.

PURPOSE: Caffeine and p-synephrine are substances usually included in commercially available products for weight loss because of their purported thermogenic effects. However, scientific information is lacking about the effects of combining these substances on substrate oxidation during exercise. The purpose of this investigation was to determine the isolated and combined effects of p-synephrine and caffeine on fat oxidation rate during exercise. METHODS: In a double-blind randomized experiment, 13 healthy subjects participated in four experimental trials after the ingestion of a capsule containing a placebo, 3 mg·kg of caffeine, 3 mg·kg of p-synephrine, or the combination of these doses of caffeine and p-synephrine. Energy expenditure and substrate oxidation rates were measured by indirect calorimetry during a cycle ergometer ramp test from 30% to 90% of V˙O2max. RESULTS: In comparison with the placebo, the ingestion of caffeine, p-synephrine, or p-synephrine + caffeine did not alter total energy expenditure or heart rate during the whole exercise test. However, the ingestion of caffeine (0.44 ± 0.15 g·min, P = 0.03), p-synephrine (0.43 ± 0.19 g·min, P < 0.01), and p-synephrine + caffeine (0.45 ± 0.15 g·min, P = 0.02) increased the maximal rate of fat oxidation during exercise when compared with the placebo (0.30 ± 0.12 g·min). The exercise intensity that elicited maximal fat oxidation was similar in all trials (~46.2% ± 10.2% of V˙O2max). CONCLUSION: Caffeine, p-synephrine, and p-synephrine + caffeine increased the maximal rate of fat oxidation during exercise compared with a placebo, without modifying energy expenditure or heart rate. However, the coingestion of p-synephrine and caffeine did not present an additive effect to further increase fat oxidation during exercise.

Acute hematological and mood perception effects of bitter orange extract (p-synephrine) consumed alone and in combination with caffeine: A placebo-controlled, double-blind study.

The purpose of this study was to examine acute hematological and mood perception responses to supplementation with p-synephrine alone and in combination with caffeine during quiet sitting. Sixteen subjects visited the laboratory on 6 occasions and were given (in randomized double-blind manner) 103-mg p-synephrine (S), 233-mg caffeine + 104-mg p-synephrine, 240-mg caffeine, 337-mg caffeine + 46-mg p-synephrine, 325-mg caffeine, or a placebo (PL). The subjects sat quietly for 3 hr while completing mood state questionnaires every 30 min. Venous blood samples were collected at baseline (pre) and 3 hr (post) to determine immune, lipid, and chemistry panels. Compared with PL, no significant supplement differences were observed during the S trial with the exception of differential time effects seen in hematocrit (decrease in PL, no change in S), triglycerides and very low-density lipoproteins (no changes in PL, significant decreases in S), and iron (no change in PL, significant elevation in S). Supplements containing caffeine showed increased feelings of attention, excitement, energy, and vigor. These data indicate that consumption of 103-mg p-synephrine does not negatively impact acute blood parameters, does not augment the effects of caffeine, or produce stimulant-like perceptual mood effects.

Safety evaluation of p-synephrine following 15 days of oral administration to healthy subjects: A clinical study.

Extracts of bitter orange (BOE, Citrus aurantium L.) and its primary protoalkaloid p-synephrine are extensively consumed as dietary supplements. p-Synephrine is also present in foods and juices prepared from various Citrus species. The safety of p-synephrine has been questioned as a result of structural similarities with ephedrine. This study assessed the cardiovascular (stimulant) and hemodynamic effects of BOE (49 mg p-synephrine) daily given to 16 healthy subjects for 15 days in a placebo-controlled, cross-over, double-blinded study. A physical evaluation by a cardiologist, as well as heart rates, blood pressures, and electrocardiograms were determined, and blood samples were drawn at baseline, and Days 5, 10, and 15. Serum levels for caffeine and p-synephrine were measured at 1 and 2 weeks. Subjects completed a 10-item health and metabolic questionnaire at baseline and on Day 15. No significant changes occurred in heart rate, electrocardiograms, systolic blood or diastolic pressures, blood cell counts, or blood chemistries in either the control or p-synephrine treated groups at any time point. No adverse effects were reported in response to the bitter orange (p-synephrine). Caffeine consumed by the participants varied markedly. Under these experimental conditions, BOE and p-synephrine were without stimulant (cardiovascular) and adverse effects.

Dose-Response Effects of p-Synephrine on Fat Oxidation Rate During Exercise of Increasing Intensity.

The aim of this investigation was to determine the effects different doses of p-synephrine on maximal fat oxidation during exercise. Seventeen healthy subjects volunteered to participate in a double-blind and randomised experimental design composed of four identical experimental trials. On four trials separated by 72 h, participants ingested a placebo or 1, 2 or 3 mg/kg of p-synephrine. After resting for 60 min to allow substance absorption, participants performed an exercise test of increasing intensity on a cycle ergometer while gas exchange was measured continuously. None of the doses of p-synephrine affected energy expenditure or heart rates during the test. The highest rate of fat oxidation with the placebo (0.35 ± 0.05 g/min) was reached at 38.0 ± 1.9% of VO2max . The ingestion of 1 mg/kg increased maximal fat oxidation to 0.47 ± 0.11 g/min (p = 0.01) but did not change the intensity at which it was obtained (42.0 ± 9.4% of VO2max ). The ingestion of 2 and 3 mg/kg of p-synephrine increased maximal fat oxidation to 0.55 ± 0.14 g/min (p < 0.01), although only 3 mg/kg slightly changed the intensity at which it was obtained (43.0 ± 9.5% of VO2max , p < 0.01). In conclusion, although all p-synephrine increased the maximal rate of fat oxidation during exercise, the highest effects were found with 2 and 3 mg/kg. Copyright © 2017 John Wiley & Sons, Ltd.

Acute cardiovascular effects of bitter orange extract (p-synephrine) consumed alone and in combination with caffeine in human subjects: A placebo-controlled, double-blind study.

The purpose was to examine cardiovascular responses to supplementation with p-synephrine alone and in combination with caffeine during quiet sitting. Sixteen subjects were given (in double-blind manner) either 103 mg of p-synephrine (S), 233 mg of caffeine +104 mg of p-synephrine (LC + S), 240 mg of caffeine (LC), 337 mg of caffeine +46 mg of p-synephrine (HC + S), 325 mg of caffeine (HC), or a placebo. The subjects sat quietly for 3 hr while heart rate (HR) and blood pressure were measured. Only HC + S and HC significantly increased mean systolic blood pressure (SBP) during the second hour and tended to increase mean SBP during the third hour. Mean diastolic blood pressure in S was significantly lower than the other trials during the first and second hours, and mean arterial pressure was significantly lower in S compared to the LC, LC + S, HC, and HC + S trials. No differences were observed in HR. Consumption of p-synephrine may acutely reduce diastolic blood pressure and mean arterial pressure and not affect SBP or HR during quiet sitting. The addition of p-synephrine to caffeine did not augment SBP or HR indicating that consumption of up to 104 mg of p-synephrine does not induce cardiovascular stress during quiet sitting.

Safety, Efficacy, and Mechanistic Studies Regarding Citrus aurantium (Bitter Orange) Extract and p-Synephrine.

Citrus aurantium L. (bitter orange) extracts that contain p-synephrine as the primary protoalkaloid are widely used for weight loss/weight management, sports performance, appetite control, energy, and mental focus and cognition. Questions have been raised about the safety of p-synephrine because it has some structural similarity to ephedrine. This review focuses on current human, animal, in vitro, and mechanistic studies that address the safety, efficacy, and mechanisms of action of bitter orange extracts and p-synephrine. Numerous studies have been conducted with respect to p-synephrine and bitter orange extract because ephedra and ephedrine were banned from use in dietary supplements in 2004. Approximately 30 human studies indicate that p-synephrine and bitter orange extracts do not result in cardiovascular effects and do not act as stimulants at commonly used doses. Mechanistic studies suggest that p-synephrine exerts its effects through multiple actions, which are discussed. Because p-synephrine exhibits greater adrenergic receptor binding in rodents than humans, data from animals cannot be directly extrapolated to humans. This review, as well as several other assessments published in recent years, has concluded that bitter orange extract and p-synephrine are safe for use in dietary supplements and foods at the commonly used doses. Copyright © 2017 The Authors Phytotherapy Research Published by John Wiley & Sons Ltd.

Effects of acute ingestion of a pre-workout dietary supplement with and without p-synephrine on resting energy expenditure, cognitive function and exercise performance.

BACKGROUND: The purpose of this study was to examine the effects of acute ingestion of a pre-workout dietary supplement (PWS) with and without p-synephrine (S) on perceptions of readiness to perform, cognitive function, exercise performance, and markers of safety. METHODS: In a randomized, double-blind, and counterbalanced manner; 25 healthy and recreationally active male and female participants ingested a flavored maltodextrin placebo (PLA), a PWS containing beta-alanine (3 g), creatine nitrate as a salt (2 g), arginine alpha-ketoglutarate (2 g), N-Acetyl-L-Tyrosine (300 mg), caffeine (284 mg), Mucuna pruiriens extract standardized for 15% L-Dopa (15 mg), Vitamin C as Ascorbic Acid (500 mg), niacin (60 mg), folate as folic acid (50 mg), and Vitamin B12 as Methylcobalamin (70 mg) with 2 g of maltodextrin and flavoring; or, the PWS with Citrus aurantium (PWS + S) extract standardized for 30% p-synephrine (20 mg). Participants had heart rate (HR), blood pressure, resting energy expenditure (REE), 12-lead electrocardiograms (ECG), perceptions about readiness to perform, cognitive function (Stroop Color-Word test), bench and leg press performance (2 sets of 10 repetitions at 70% of 1RM and 1 set to failure), and Wingate anaerobic capacity (WAC) sprint performance determined as well as donated blood samples prior to and/or following exercise/supplementation. Data were analyzed by MANOVA with repeated measures as well as mean changes from baseline with 95% confidence intervals (CI). RESULTS: No clinically significant differences were observed among treatments in HR, blood pressure, ECG, or general clinical blood panels. There was evidence that PWS and PWS + S ingestion promoted greater changes in REE responses. Participants reported higher perception of optimism about performance and vigor and energy with PWS and PWS + S ingestion and there was evidence that PWS and PWS + S improved changes in cognitive function scores from baseline to a greater degree than PLA after 1 or 2 h. However, the scores in the PWS + S treatment did not exceed PLA or PWS responses at any data point. No statistically significant differences were observed among treatments in total bench press lifting volume, leg press lifting volume or WAC sprint performance. CONCLUSIONS: Within the confines of this study, ingestion of PWS and/or PWS + S prior to exercise appears to be well-tolerated when consumed by young, healthy individuals. The primary effects appear to be to increase REE responses and improve perceptions about readiness to perform and cognitive function with limited to no effects on muscular endurance and WAC. The addition of 20 mg of p-synephrine to the PWS provided limited to no additive benefits. TRIAL REGISTRATION: This trial (NCT02952014) was retrospectively registered on September 13th 2016.

Acute p-synephrine ingestion increases fat oxidation rate during exercise.

AIMS: p-Synephrine is a protoalkaloid widely used in dietary supplements for weight management because of its purported thermogenic effects. However, there is a lack of scientific information about its effectiveness to increase fat metabolism during exercise. The purpose of this investigation was to determine the effects of an acute ingestion of p-synephrine on fat oxidation at rest and during exercise. METHODS: In a double-blind, randomized and counterbalanced experimental design, 18 healthy subjects performed two acute experimental trials after the ingestion of p-synephrine (3 mg kg(-1) ) or after the ingestion of a placebo (cellulose). Energy expenditure and fat oxidation rates were measured by indirect calorimetry at rest and during a cycle ergometer ramp exercise test (increases of 25 W every 3 min) until volitional fatigue. RESULTS: In comparison with the placebo, the ingestion of p-synephrine did not change energy consumption (1.6 ± 0.3 vs. 1.6 ± 0.3 kcal min(-1) ; P = 0.69) or fat oxidation rate at rest (0.08 ± 0.02 vs. 0.10 ± 0.04 g min(-1) ; P = 0.15). However, the intake of p-synephrine moved the fat oxidation-exercise intensity curve upwards during the incremental exercise (P < 0.05) without affecting energy expenditure. Moreover, p-synephrine increased maximal fat oxidation rate (0.29 ± 0.15 vs. 0.40 ± 0.18 g min(-1) ; P = 0.01) during exercise although it did not affect the intensity at which maximal fat oxidation was achieved (55.8 ± 7.7 vs. 56.7 ± 8.2% VO2peak ; P = 0.51). CONCLUSIONS: The acute ingestion of p-synephrine increased the fat oxidation rate while it reduced the carbohydrate oxidation rate when exercising at low-to-moderate exercise intensities.