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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.

To examine the safety and efficacy of citrus aurantium, an herb now commonly used as a substitute for ephedra in dietary supplements marketed to promote weight loss, we conducted a systematic review. An extensive search of MEDLINE, EMBASE, BIOSIS, and the Cochrane Collaboration Database identified only 1 eligible randomized placebo controlled trial, which followed 20 patients for 6 weeks, demonstrated no statistically significant benefit for weight loss, and provided limited information about the safety of the herb.

p-Synephrine is deemed a safe and effective substance to increase fat utilization during exercise of low-to-moderate intensity in men but not in women. Additionally, the existence of a diurnal variation in substrate utilization has been documented during exercise with enhanced fat oxidation in the evening compared with early morning. However, it remains unknown whether there is an interaction between the effect of p-synephrine and the time of the day on fat oxidation during exercise. This study aimed to evaluate the effect of the acute ingestion of 3 milligram of p-synephrine per kilogram of body mass (mg/kg) on fat oxidation during exercise of increasing intensity when the exercise is performed in the morning vs. the evening. Using a randomized, double-blind, placebo-controlled experimental design, 16 healthy and active women performed four identical exercise trials after the ingestion of 3 mg/kg of p-synephrine and 3 mg/kg of a placebo (cellulose) both in the morning (8-10 am) and in the evening (5-7 pm). In the exercise trials, the substances were ingested 60 min before an incremental test on a cycle ergometer with 3 min stages at workloads from 30 to 80% of maximal oxygen uptake (VO2max). Substrate oxidation rates were measured by indirect calorimetry. In each trial, the maximum rate of fat oxidation (MFO) and the intensity that elicited MFO (Fatmax) were measured. A two-way analysis of variance (time-of-the day × substance) was used to detect differences among the trials. With the placebo, MFO was 0.25 ± 0.11 g/min in the morning and 0.24 ± 0.07 g/min in the evening. With p-synephrine, MFO was 0.26 ± 0.09 g/min in the morning and 0.21 ± 0.07 g/min in the evening. There was no main effect of substance (p = 0.349), time of day (p = 0.186) and the substance × time of day (p = 0.365) on MFO. Additionally, Fatmax was reached at a similar exercise intensity with the placebo (41.33 ± 8.34% VO2max in the morning and 44.38 ± 7.37% VO2max in the evening) and with p-synephrine (43.33 ± 7.24% VO2max in the morning and 45.00 ± 7.43% VO2max in the evening), irrespective of the time of day with no main effect of substance (p = 0.633), time of day (p = 0.191), or interacti

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 aim of this study was to investigate the acute effects of p-synephrine ingestion on substrate oxidation during exercise in elite cyclists. Fifteen elite cyclists volunteered to participate in a double blind, crossover, randomized and placebo-controlled experimental trial. During two different trials, participants either ingested a placebo (cellulose) or 3 mg/kg of p-synephrine. After 60 min for substances absorption, participants performed an incremental maximal cycle ergometer test until volitional fatigue (25 W/min). Breath-by-breath gas exchange data was continuously recorded during the entire test to estimate energy expenditure, carbohydrate oxidation, and fat oxidation rates by stoichiometric equations. Heart rate was continuously measured by using a heart rate monitor. The ingestion of p-synephrine had no significant effects on energy expenditure (F = 0.71, P = 0.40) or heart rate (F = 0.66, P = 0.43) during exercise. However, there was a main effect of p-synephrine to increase the rate of fat oxidation over the placebo (F = 5.1, P = 0.04) and the rate of fat oxidation was higher with p-synephrine in the following loads: 45 ± 2%, 51 ± 3%, 62 ± 3%, 67 ± 4%, 79 ± 5% and 85 ± 5% of the maximum wattage obtained in the test (all P < 0.05). The ingestion of p-synephrine did not modify the maximal rate of fat oxidation during the ramp test (mean value; 95%CI = 0.91; 0.79-1.03 vs 1.01; 0.91-1.11 g/min, respectively, P = 0.06) nor the exercise intensity at which maximal fat oxidation was achieved (i.e. Fatmax = 49; 48-53 vs 50; 47-51% Wmax, P = 0.52). Acute p-synephrine ingestion moved the fat oxidation-exercise intensity curve upwards during an incremental cycling test without affecting Fatmax.

This study aimed to assess the cutaneous analgesic effect of the lidocaine-synephrine combination and its underlying α-adrenergic receptor-mediated mechanism in comparison with phenylephrine. Cutaneous analgesia after subcutaneous drug injection was assessed by inhibition of the cutaneous trunci muscle reflex in response to needle pinpricks on the shaved dorsal skin of Sprague-Dawley rats. Synephrine, like the local anesthetic lidocaine, is capable of inducing cutaneous analgesia but is less potent. On an equipotent basis (ED25, ED50 [50% effective dose], and ED75), the block duration induced by synephrine or phenylephrine was longer than that induced by lidocaine (p < 0.01). When combined with lidocaine, the ED50 for synephrine decreased from 326 (183-579) μmol/kg to 141 (128-156) μmol/kg (p < 0.01), and for phenylephrine, it decreased from 15.8 (9.0-27.9) μmol/kg to 6.2 (5.9-6.6) μmol/kg (p < 0.01). Lidocaine (ED95) in combination with either synephrine (52 μmol/kg) or phenylephrine (1.6 μmol/kg) prolonged the duration of action (p < 0.001), while phentolamine (0.3 μmol/kg) reversed these effects. We concluded that synephrine produces dose-dependent cutaneous analgesia that is less potent but longer-lasting than lidocaine. The enhanced analgesic effects of the lidocaine-synephrine and lidocaine-phenylephrine combinations are mediated through α-adrenergic receptor activation. © 2026 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.

4-Hydroxynonenal (4-HNE), a highly reactive α,β-unsaturated aldehyde, is involved in the pathogenesis of several chronic diseases. In this study, we investigated the kinetics of 4-HNE with cyanidin-3-O-glucoside (C3G) and elucidated the pathways of C3G-4-HNE adduct formation using UHPLC-MS/MS. SYN was identified as an enhancer that improves the 4-HNE clearance rate and promotes adduct formation. When combined with SYN, the clearance rate of 5 mM C3G (3/2 mM) reached 90% within 8 h (12 h/24 h), compared to less than 60% for C3G alone within 24 h. UHPLC-MS/MS analysis revealed that C3G and its metabolite, phloroglucinol aldehyde (PGA), form 4-HNE adducts in a dose-dependent manner in mouse feces. Compared to the use of C3G alone (200/400 mg/kg bw), the combination with SYN (40/80 mg/kg bw) significantly enhanced the formation of 4-HNE adducts, increasing it by 7.19-8.27-fold. This synergy suggests a novel strategy for enhancing 4-HNE clearance in vivo.

BACKGROUND: p-Synephrine (p-Syn), a natural alkaloid isolated from Citrus aurantium L., promotes fat oxidation and is therefore widely used as a weight loss dietary supplement. It was recently reported to exert a potent antidepressant effect. However, its molecular targets remain undefined. Gastrodin (Gas), extracted from Gastrodia elata Blume, exerts antidepressant effects by targeting Melatonin Receptor 1A (MT1). PURPOSE: This study aimed to evaluate whether MT1 is a target of p-Syn, and to verify the antidepressant effects of p-Syn and Gas. METHODS: Network pharmacology was applied to predict potential targets and associated signaling pathways for p-Syn and Gas. Molecular Docking simulations were employed to predict the possible binding sites of MT1 with p-Syn. Solvent-induced Protein Precipitation (SIP) and Fluorescence Correlation Spectroscopy (FCS) were employed to validate p-Syn's binding affinity with MT1. Cellular Thermal Shift Assay (CETSA) was used to confirm the predicted key binding sites in exogenously overexpressed site-mutated MT1. of Extracellular regulated protein kinases (ERK) and cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) downstream of MT1, following treatment with p-Syn or Gas, or the synergistic use of both, was investigated by Western blotting. RESULTS: Using a network pharmacology approach and in vitro assays, we found that both p-Syn and Gas bind to MT1, activate the ERK/CREB signaling pathway, and up-regulate BDNF. In vivo assays showed that p-Syn alleviated Reserpine (Res)-induced depression-like symptoms in AB zebrafish larvae and C57 mice. Furthermore, p-Syn and Gas showed a remarkable synergistic effect. CONCLUSION: This study identifies a novel target for p-Syn and provides new insights into the antidepressant mechanisms of p-Syn and Gas that may contribute to the clinical application of these compounds in the development of new drugs for the treatment of depression.

ETHNOPHARMACOLOGICAL RELEVANCE: Citri Reticulatae Pericarpium (Rutaceae, CRP), commonly called as Chenpi () in Chinese, is most frequently used as a qi-regulating drug in thousands of Chinese medicine prescriptions. CRP is found mainly in major citrus-producing areas such as the Guangdong, Guangxi, Sichuan, Fujian, and Zhejiang Provinces of China. Since thousands of years in China, CRP has been used widely in clinical practice to treat nausea, vomiting, indigestion, anepithymia, diarrhea, cough, expectoration, and so on. Currently, CRP is listed in the Pharmacopoeia of the People's Republic of China. The present paper reviews the botany, ethnopharmacology, phytochemistry, pharmacology, quality control, and toxicology of CRP. MATERIALS AND METHODS: Information on CRP was gathered from various sources including the books on traditional Chinese herbal medicine; scientific databases including Elsevier, PubMed, and ScienceDirect; Baidu Scholar; CNKI; and others and from different professional websites. RESULTS: Approximately 140 chemical compounds have been isolated and identified from CRP. Among them, volatile oils and flavonoids are generally considered as the main bioactive and characteristic ingredients. CRP possesses wide pharmacological effects such as having a beneficial effect on the cardiovascular, digestive, and respiratory systems, antitumor, antioxidant, and anti-inflammatory properties; and a protective effect on the liver and nerve. Moreover, hesperidin is chosen as an indicator in the quantitative determination of CRP, and the quantity of aflatoxin in CRP must not exceed the standard limit mentioned in the pharmacopoeia. CONCLUSIONS: In brief, CRP has a warming nature, and hence, it can be used in harmony with a lot of medicines. CRP not only exhibits its effects individually but also aids other medicines exhibit a better effect. CRP can be consumed with tea, food, alcohol, and medicine. Irrespective of the form it is being consumed, CRP not only shows a synergistic effect but also has strengths on its own. Modern pharmacological studies have demonstrated that CRP has marked bioactivities, especially on the diseases of the digestive and respiratory sys

When safety concerns forced the removal of ephedra from the market, other botanicals, including Citrus aurantium or bitter orange (BO) were used as replacements. A major component of the BO extract is synephrine, a chemical that is structurally similar to ephedrine. Because ephedrine has cardiovascular effects that may be exacerbated during physical exercise, the purpose of this study was to determine whether extracts containing synephrine produced adverse effects on the cardiovascular system in exercising rats. Sprague-Dawley rats were dosed daily by gavage for 28 days with 10 or 50 mg of synephrine/kg body weight from one of two different extracts; caffeine was added to some doses. The rats ran on a treadmill for 30 min/day, 3 days/week. Heart rate, blood pressure, body temperature, and QT interval were monitored. Both doses of both extracts significantly increased systolic and diastolic blood pressure for up to 8 h after dosing. Effects on heart rate and body temperature appeared to be due primarily to the effects of caffeine. These data suggest that the combination of synephrine, caffeine, and exercise can have significant effects on blood pressure and do not appear to be effective in decreasing food consumption or body weight.

We investigated the effects of Evodiae Fructus and synephrine, one of the components of Evodiae Fructus, on blood vessels. We found that Evodiae Fructus (1 x 10(-6) - 3 x 10(-4) g/mL) had constrictive effects on rat aorta. The vasoconstrictive effects of Evodiae Fructus were significantly inhibited by pretreatment with prazosin (adrenergic alpha(1)-receptor antagonist), BRL15572 [5-hydroxytryptamine (5-HT)(1D) antagonist], and ketanserin (5-HT(2A) antagonist), but its vasoconstrictive effects were not inhibited by pretreatment with SB216641 (5-HT(1B) antagonist) or propranolol (adrenergic beta-receptor antagonist). These results suggest that Evodiae Fructus constricts rat aorta via adrenergic and serotonergic receptors. We also investigated the constrictive effects of synephrine on blood vessels. The vasoconstrictive effects of synephrine (1 x 10(-7) - 3 x 10(-5) mol/L) were significantly inhibited by pretreatment with prazosin, BRL15572, and ketanserin. However, its constrictive effects were not inhibited by pretreatment with SB216641 and propranolol. The pA(2) values of prazosin or ketanserin were nearly equal between Evodiae Fructus and synephrine. Because the constrictive effects of both Evodiae Fructus and synephrine were exerted via adrenergic alpha(1)-receptors and serotonergic (5-HT(1D) and 5-HT(2A)) receptors, synephrine may be one of the important components in the constrictive effects of Evodiae Fructus.

AIM: To investigate the anti-asthmatic mechanisms of the traditional Chinese medicine Pericarpium citri reticulatae (PCR). METHODS: The alkaloid section (AS) of PCR was extracted using an ion exchange resin, separated, and purified into different fractions by semi-preparative HPLC. These fractions were screened for beta2-adrenergic receptor (beta(2)AR) agonistic activity using rat beta(2)AR-transfected CHO-CRE-EGFP cells. AS and its isolated components were characterized by ultra-performance liquid chromatography/quadrupole time-of-flight MS (UPLC/Q-Tof MS) and were evaluated for their spasmolytic and antitussive activities both in vitro and in vivo in a guinea pig model. RESULTS: We demonstrated that the AS component responsible for activating beta(2)AR signaling was synephrine. Both AS and synephrine showed significant spasmolytic effects on acetylcholine chloride (ACh)-induced contractions in isolated guinea pig trachea, and they protected against histamine-induced experimental asthma by prolonging the latent period. We further identified stachydrine as the antitussive component that could significantly reduce citric acid-induced coughing. The combination of these two bioactive compounds had a more potent spasmolytic activity in comparison with the single use of synephrine or stachydrine. CONCLUSION: We conclude that synephrine and stachydrine are the key components of AS that mediate asthma relief due to their synergism when used in combination.

The effects of dietary chemopreventive citrus phytochemicals on the drug efflux transporters P-glycoprotein (ABCB1) and multidrug resistance protein 1 (MRP1, ABCC1) were investigated using P-glycoprotein-overexpressing human carcinoma KB-C2 cells and human MRP1 gene-transfected KB/MRP cells. The effects of natural chemopreventive citrus phytochemicals, such as auraptene, nobiletin, citral, citronellal, limonene, limonin, and synephrine were examined. The accumulation of daunorubicin, a fluorescent substrate of P-glycoprotein, increased in the presence of auraptene and nobiletin in KB-C2 cells. Nobiletin also increased the accumulation of calcein, a fluorescent substrate of MRP1, in KB/MRP cells. The ATPase activity of P-glycoprotein was stimulated by auraptene and nobiletin. The ATPase activity of MRP1 was stimulated by nobiletin. These results suggest that chemopreventive citrus phytochemicals, such as nobiletin found in oranges, have inhibitory effects on P-glycoprotein and/or MRP1, and may cause food-drug interactions.

196. S Afr Med J. 2008 Jul;98(7):496. Citrus aurantium--beware of the bitter orange. Louw VJ, Louw H. Comment on S Afr Med J. 2008 May;98(5):372-3.

197. Health News. 2004 Dec;10(12):9. Bitter orange weight loss products may not be safe. [No authors listed]