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.

USAKefir is a milk-derived product prepared by the incubation of kefir 'grains' with defatted milk. Various studies have been published on the therapeutic effects of kefir. However, few controlled studies and little information on the antibacterial, antifungal and antitumoural activities of kefir have been published. Therefore, these activities associated with kefir were investigated. The daily intraperitoneal administration of 0.50 mL kefir for 20 days to mice; containing transplanted fusiform cell carcomas resulted in a significant decrease in tumour size. Kefir-induced disappearance of tumoural necrosis was also evident. With respect to the antibacterial activity of kefir, the greatest activity was exhibited against gram-positive coccus, staphylococcus, and gram-positive bacillus. Kefir 'grains' showed higher antibacterial activity than kefir. Kefir also demonstrated antifungal activity against Candida, Saccharomyces, Rhodotorulo, Torulopsis, Microsporum and Trichopyton species. The results demonstrate that kefir possesses antibacterial, antifungal and antineoplastic activities, and provides credence to the folklorec use of kefir for a variety of infectious and neoplastic diseases.

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, β‐1 and β‐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.

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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.

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.

BackgroundNumerous health benefits have been demonstrated for curcumin which is extracted from turmeric (Curcuma longa L). However, due to its poor absorption in the free form in the gastrointestinal tract and rapid biotransformation, various formulations have been developed to enhance its bioavailability. Previous studies indicate that the free form of curcumin is more bioactive than its conjugated counterparts in target tissues. Most curcumin pharmacokinetics studies in humans designed to assess its absorption and bioavailability have measured and reported total (free plus conjugated) curcumin, but not free, bioactive curcumin in the plasma because enzymatic hydrolysis was employed prior to its extraction and analysis. Therefore, the bioavailability of free curcumin cannot be determined.MethodsEight human subjects (4 male, 4 female) consumed a single dose of 400 mg curcumin in an enhanced absorption formulation, and blood samples were collected over 6 h. Plasma was treated either with or without glucuronidase/sulfatase prior to extraction. Curcumin and its major metabolites were analyzed using HPLC-tandem mass spectrometry. In addition, the literature was searched for pharmacokinetic studies involving curcumin using PubMed and Google Scholar, and the reported bioavailability data were compared based on whether hydrolysis of plasma samples was used prior to sample analysis.ResultsHydrolysis of blood plasma samples prior to extraction and reporting the results as “curcumin” obscures the amount of free, bioactive curcumin and total curcuminoids as compared to non-hydrolyzed samples. As a consequence, the data and biological effects reported by most pharmacokinetic studies are not a clear indication of enhanced plasma levels of free bioactive curcumin due to product formulations, leading to a misrepresentation of the results of the studies and the products when enzymatic hydrolysis is employed.ConclusionsWhen enzymatic hydrolysis is employed as is the case with most studies involving curcumin products, the amount of free bioactive curcumin is unknown and cannot be determined. Therefore, extreme caution is warranted in interpreting published analytical results from biological samples involving ingestion of curcumin-containing products.Trial registrationClinicalTrails.gov, trial identifying number NCT04103788, September 24, 2019. Retrospectively registered.

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