Fig 3 - uploaded by Sidney Stohs
Content may be subject to copyright.
Source publication
This review summarizes the published as well as unpublished human studies involving Citrus aurantium (bitter orange) extract and its primary protoalkaloid p-synephrine, providing information and an assessment of the safety and efficacy of these widely used products. The results of over 20 studies involving a total of approximately 360 subjects that...
Context in source publication
Context 1
... limited number of studies have been con- ducted with p-synephrine and bitter orange extracts without the addition of various other ingredients and herbal products. The issue of safety and efficacy is further clouded and complicated by the structural similarity of p-synephrine to ephedrine (Figure 3) and other biogenic amines, in spite of the fact that the pharmacokinetics of the these compounds and their receptor binding specificities are vastly different due to significant structural and stereochemical differ- ences [10,11]. As a consequence, markedly different pharmacological properties should be anticipated. ...
Similar publications
Caffeine is naturally found in plant products such as coffee beans, cocoa beans and tea leaves. In this study, caffeine molecular imprinted polymer (MIP) was synthesized by dissolving 1 mmol caffeine and 4 mmol monomer, methacrylic acid (MAA) and 1mmol ethylene glycol dimethacrylate (EDMA) as the crosslinker and benzoyl peroxide (BOP) as the initia...
Citations
... Citrus aurantium and synephrine are known for their therapeutic potential in thermogenesis stimulation. However, studies that indicate C. aurantium and synephrine as inducers of weight loss and thermogenic action in adipose tissue are still scarce (33). Moreover, the most of them are carried out in combination with other medicines and plants or to assess its toxicity (28,34,35). ...
Introduction and aims
Obesity is a multifactorial condition with high health risk, associated with important chronic disorders such as diabetes, dyslipidemia, and cardiovascular dysfunction. Citrus aurantium L. (C. aurantium) is a medicinal plant, and its active component, synephrine, a β-3 adrenergic agonist, can be used for weight loss. We investigated the effects of C. aurantium and synephrine in obese adolescent mice programmed by early postnatal overfeeding.
Methods
Three days after birth, male Swiss mice were divided into a small litter (SL) group (3 pups) and a normal litter (NL) group (9 pups). At 30 days old, SL and NL mice were treated with C. aurantium standardized to 6% synephrine, C. aurantium with 30% synephrine, isolated synephrine, or vehicle for 19 days.
Results
The SL group had a higher body weight than the NL group. Heart rate and blood pressure were not elevated. The SL group had hyperleptinemia and central obesity that were normalized by C. aurantium and synephrine. In brown adipose tissue, the SL group showed a higher lipid droplet sectional area, less nuclei, a reduction in thermogenesis markers related to thermogenesis (UCP-1, PRDM16, PGC-1α and PPARg), and mitochondrial disfunction. C. aurantium and synephrine treatment normalized these parameters.
Conclusion
Our data indicates that the treatment with C. aurantium and synephrine could be a promising alternative for the control of some obesity dysfunction, such as improvement of brown adipose tissue dysfunction and leptinemia.
... The p-synephrine isomer is widely used as a dietary supplement for weight loss since it promotes fat oxidation [1,6]. The safety of p-synephrine to be used in thermogenic dietary supplements was demonstrated in multiple studies [7,26,28,29]. m-Synephrine, also called phenylephrine, is considered to be the most potent adrenergic agonist of the synephrine at α1-adrenoreceptors (α1-AR) as compared to other isomers [1]. The o-synephrine isomer is not found in dietary supplements, and no pharmacological effect of it on humans has been revealed [30]. ...
This review is focused on synephrine, the principal phytochemical found in bitter orange and other medicinal plants and widely used as a dietary supplement for weight loss/body fat reduction. We examine different aspects of synephrine biology, delving into its established and potential molecular targets, as well as its mechanisms of action. We present an overview of the origin, chemical composition, receptors, and pharmacological properties of synephrine, including its anti-inflammatory and anti-cancer activity in various in vitro and animal models. Additionally, we conduct a comparative analysis of the molecular targets and effects of synephrine with those of its metabolite, selective glucocorticoid receptor agonist (SEGRA) Compound A (CpdA), which shares a similar chemical structure with synephrine. SEGRAs, including CpdA, have been extensively studied as glucocorticoid receptor activators that have a better benefit/risk profile than glucocorticoids due to their reduced adverse effects. We discuss the potential of synephrine usage as a template for the synthesis of new generation of non-steroidal SEGRAs. The review also provides insights into the safe pharmacological profile of synephrine.
... Anti-obesity Activity C. aurantium is considered a sport enhancer and swift weight loss ingredient and as an alternative therapeutic dietary supplement as it contains compounds such as flavonoids and polyphenols both of which can reduce the accumulation of lipids [108]. Stohs et al. [109] in their review of human clinical trials involving the use of C. aurantium and its alkaloid p-synephrine observed that from over 20 studies carried out with over 50% of the 360 test subjects were obese. P-synephrine was given in combination with caffeine, guarana, green tea, gingko, ginseng, and yerba mate making it difficult to ascertain if weight loss was as a result of p-synephrine or the other components; be that as it may, it was deduced that C. aurantium is the most likely causative agent for weight loss because of its effects on metabolic processes including increase in metabolic rate, appetite suppression, and lipolysis. ...
Citrus aurantium, commonly referred to as sour orange or bitter orange, holds significant importance both in biological and economic terms. Throughout history, humans have turned to nature in their pursuit of health and wellness. Among the plants that have historically played a role in enhancing fitness, Citrus
aurantium stands out. A diverse array of phytochemical constituents present in Citrus aurantium have been closely tied to its various biological activities, encompassing areas such as gastrointestinal disorders, insomnia, headaches, cancer treatment, antiseptic properties, antioxidant effects, and antispasmodic effects. Beyond its pharmacological relevance, Citrus aurantium also boasts numerous non-pharmacological applications that make it particularly intriguing. It serves as a food preservative agent, contributes to aromatherapy practices, acts
as a pesticide, provides raw materials for the pulp and paper industry, lends its aromatic qualities to the food processing and cosmetics sectors, and offers potential as an anti-aging agent. Despite its impressive array of properties, the utilization of Citrus aurantium and its derivatives has been linked to certain
unwanted side effects. While some studies have largely cleared the plant of safety concerns, others have cast doubt on its safety. This chapter delves into the complex aspects surrounding the safety of Citrus aurantium’s photochemistry and its derived products. Ultimately, the chapter advocates for the ongoing use of this plant, but with a careful awareness of its limitations to prevent any undesirable effects.
... Aloe Vera (Aloe barbadensis): Aloe vera is known for its laxative properties, and some research has explored its potential in weight loss. It may help with temporary weight reduction through its cleansing effects on the digestive system [22]. 14. ...
... Aloe vera gel has shown potential for weight loss and reducing body fat in animal studies. [22] Some animal studies have suggested that Aloe vera gel may reduce body fat and body weight, possibly by improving lipid metabolism. [22] Turmeric (Curcuma longa) ...
... [22] Some animal studies have suggested that Aloe vera gel may reduce body fat and body weight, possibly by improving lipid metabolism. [22] Turmeric (Curcuma longa) ...
Obesity has become a global health crisis with substantial implications for public health. In the past 50 years, significant advancements have been made in the treatment of disorders like hypertension, adult-onset diabetes, and increased cholesterol that are directly related to obesity. However, the disease of obesity has proven to be mostly resistant to treatments, and anti-obesity drugs (AOMs) frequently have questionable safety and poor efficacy. Here, we give a summary of the history of AOM development with an emphasis on the lessons learned and current challenges. The search for next-generation AOMs that look capable of safely accomplishing significant and sustained body weight loss is motivated by recent developments, including improved knowledge of the molecular gut-brain communication. The exploration of medicinal plants for their anti-obesity potential has gained momentum due to their perceived safety and cultural acceptance.
... Stohs et. [40] summarized the results of 23 human studies assessing the efficacy and safety of these products, and concluded that p-synephrine, alone or in combination, does not lead to significant side effects such as increase in heart rate or blood pressure. Nevertheless, with the increase in consumption, the number of reported side effects has increased significantly [40]. ...
... [40] summarized the results of 23 human studies assessing the efficacy and safety of these products, and concluded that p-synephrine, alone or in combination, does not lead to significant side effects such as increase in heart rate or blood pressure. Nevertheless, with the increase in consumption, the number of reported side effects has increased significantly [40]. The proposed reason for this discrepancy was found in the fact that supplements for weight loss were almost always a combination of two or more active ingredients with a similar stimulating effect, so that their synergistic effect could easily occur (the combination of synephrine and caffeine was reported in 33 cases, 20 of which contained a high dose of caffeine). ...
Health concerns associated with the consumption of food supplements rise in parallel with the rise in the popularity and market availability of these products. In pursuit of data related to the unauthorized presence of pharmaceuticals in food supplements, the Rapid Alert System for Food and Feed (RASFF) database was searched for the 2011–2022 period. The most “popular” pharmaceuticals for the adulteration of food supplements were phosphodiesterase-5 inhibitors (235 records); anorexics and laxatives (76), including sibutramine and its active metabolite N-didesmethyl sibutramine, phenolphthalein and 2,4-dinitrophenol; stimulants, among which 1,3-dimethylamine (97), and synephrine (53) were the most numerous; nootropic drugs (24); anabolics and prohormones (16); and cannabinoid cannabidiol (14) (pending authorization as a novel food ingredient). Over 65% of notifications of interest were classified as serious risks, and over 80% of these were alert or border rejection notifications, mainly generated as a result of official control on the market. The alarming number of RASFF notifications should be considered a public health issue, demanding clear and targeted recommendation for action for the legislature and authorities. A harmonized nutrivigilance system should be considered as a tool to detect and scrutinize the adverse health effects of food supplements, along with measures to improve their safety, quality, and testing.
... 155 It has been reported that b-synephrine causes significant increases in resting metabolic rate in humans, and its use for up to 12 weeks can result in moderate weight loss. 156 Stohs et al 25 examined the effect of the consumption of p-synephrine alone or in combination with some flavonoids on the resting metabolic rate, and they reported that 50 mg of p-synephrine supplementation alone increased the resting metabolic rate by 6.9% compared with placebo. Jung et al 157 reported that 20 mg of p-synephrine supplementation before training by 25 participants increased the respiratory quotient significantly compared with the placebo. ...
Citrus fruits are widely consumed for their nutritional and health benefits. They belong to the Rutaceae and have many varieties, such as sweet orange (Citrus sinensis), which is the most popular. Citrus fruits are rich in water (>80%), dietary fiber, and vitamins. They also contain bioactive components, which may modulate energy metabolism and lipid oxidation through various mechanisms. These mechanisms include stimulating β3-adrenergic receptors, increasing mitochondrial biogenesis and thermogenesis, activating AMP kinase and peroxisome proliferator-activated receptor-gamma coactivator-1α pathways, inhibiting lipogenesis and lipid accumulation, and inducing browning of white adipose tissue. This review summarizes the mechanisms and outcomes of citrus fruits and their metabolites on energy metabolism and body weight in different experimental models. The literature was searched for in vitro and in vivo animal and human studies that investigated the effects of citrus consumption on energy expenditure, thermogenesis, adipogenesis, and lipid accumulation. Citrus fruits and their metabolites have shown promising effects on energy metabolism and lipid oxidation in in vitro and in vivo animal studies. However, the evidence from human studies is limited and inconsistent. Possible reasons for the discrepancy are briefly discussed, and knowledge gaps and research needs are identified for future studies. Citrus fruits may have beneficial effects on energy metabolism and body weight, but more rigorous and well-designed human trials are needed to confirm their efficacy and safety.
... The clinical trial investigated the effects of citrus species on obesity, weight loss, metabolic and cardiovascular indices are listed in Table 4. As an example, 12 weeks of consumption of p-synephrine alone or as an ingredient of polyherbal products increased resting metabolic rate, energy expenditure, and modestly improved weight loss [78]. In another study, consumption of p-synephrine (3 mg/kg) was ineffective in increasing performance in competitive sprint athletes [79]. ...
s u m m a r y Fruits, flowers, leaves, essential oils, hydrosols, and juices of citrus spp. Are utilized to prepare various forms of food products. Along with their nutritional values, in the health industry, different parts of the plants of the citrus genus have been used as supplements or remedies to prevent or control diseases. This review focused on reported meta-analyses and clinical trials on the health benefits of citrus plants as functional foods. Also, chemical compounds of various citrus species were reviewed. The following information sources were used for data collection: Google Scholar, the Web of Science, Scopus, and PubMed. Various keywords, including "citrus AND chemical compounds," "citrus AND phytochemicals," "citrus species," "citrus AND meta-analysis," "nutritional and therapeutical values of citrus spp.," "clinical trials AND citrus," "clinical trials AND Rutaceae," "health benefits of citrus spp.," "citrus edible or non-edible applications," and scientific names of the citrus plants were utilized to collect data for the review. The scientific name and common name of all twenty-eight citrus species, along with any of the above keywords, were also searched in the mentioned databases. Scientific papers and data sources were sought to review and discuss the citrus plant's nutritional and therapeutic importance. Several meta-analyses and clinical trials have reported beneficial effects of citrus spices on a variety of cancer risks, cardiovascular risk factors, neurologic disorders, urinary tract conditions, and gastrointes-tinal tract conditions. They have shown anxiolytic, antimicrobial, and pain-alleviating effects. Some of them can be helpful in managing obesity and cardiovascular risk factors.
... The clinical trial investigated the effects of citrus species on obesity, weight loss, metabolic and cardiovascular indices are listed in Table 4. As an example, 12 weeks of consumption of p-synephrine alone or as an ingredient of polyherbal products increased resting metabolic rate, energy expenditure, and modestly improved weight loss [78]. In another study, consumption of p-synephrine (3 mg/kg) was ineffective in increasing performance in competitive sprint athletes [79]. ...
Fruits, flowers, leaves, essential oils, hydrosols, and juices of citrus spp. Are utilized to prepare various
forms of food products. Along with their nutritional values, in the health industry, different parts of the
plants of the citrus genus have been used as supplements or remedies to prevent or control diseases. This
review focused on reported meta-analyses and clinical trials on the health benefits of citrus plants as
functional foods. Also, chemical compounds of various citrus species were reviewed. The following information
sources were used for data collection: Google Scholar, the Web of Science, Scopus, and
PubMed. Various keywords, including “citrus AND chemical compounds,” “citrus AND phytochemicals,”
“citrus species,” “citrus AND meta-analysis,” “nutritional and therapeutical values of citrus spp.," “clinical
trials AND citrus,” “clinical trials AND Rutaceae,” “health benefits of citrus spp.," “citrus edible or nonedible
applications,” and scientific names of the citrus plants were utilized to collect data for the review.
The scientific name and common name of all twenty-eight citrus species, along with any of the
above keywords, were also searched in the mentioned databases. Scientific papers and data sources were
sought to review and discuss the citrus plant's nutritional and therapeutic importance.
Several meta-analyses and clinical trials have reported beneficial effects of citrus spices on a variety of
cancer risks, cardiovascular risk factors, neurologic disorders, urinary tract conditions, and gastrointestinal
tract conditions. They have shown anxiolytic, antimicrobial, and pain-alleviating effects. Some of
them can be helpful in managing obesity and cardiovascular risk factors.
... C. aurantium'un antimikrobiyal, antioksidan, sitotoksik, anksiyolitik ve antidiyabetik etkilerinin yanında kilo kaybı ve spor performansı arttırıcı etkisi de merak konusu olmuştur. C. aurantium ekstratının obezite üzerine etkilerinin araştırıldığı bir çalışmada sonuçlar p-Synephrine'in tek başına veya kombinasyon ürünleri (p-sinefrin ile birden çok bileşen içeren bir kombinasyon ürünü) halinde altı ila 12 hafta verildiğinde metabolik hızı ve enerji tüketimini arttırdığı ve kilo kaybını desteklediği göstermiştir (Stohs, Preuss & Shara, 2012). ...
Cancer is the leading cause of morbidity and mortality in the world. It has been reported that the incidence of new cancer cases in the world is 19.3 million with a death rate of 10 million in 2020. Chemotherapeutic drugs are used in cancer treatment. The most well-known anthracycline is doxorubicin. The anthracycline antibiotic doxorubicin (Adriamycin; Doxorubicin) was first produced in the 1960s from Streptomyces peucetius (Arcamone et al., 1969). Doxorubicin has been used as an anticancer drug for over forty years (Warpe et al., 2015). It is considered one of the most effective broad-spectrum anti-cancer anthracycline antibiotics when administered alone or in combination with other anti-cancer agents. It has been determined to be highly effective against various types of cancer, including malignancies (bladder, breast, lung, etc.), hematological neoplasia (Hodgkin's disease and non-Hodgkin lymphomas, and pediatric leukemia) (Wenningmann et al.,2019). Oxidative stress is produced due to the imbalance between reactive oxygen species generation in response to cell damage and endogenous antioxidant activation, leading to myocardial toxicity. Increased oxidative stress and antioxidant factor deficiency play an important role in doxorubicin-induced cardiotoxicity. By increasing the production of reactive oxygen species, doxorubicin impairs mitochondrial function and causes mutations in mitochondrial DNA. Cardiac damage due to mitochondrial damage and oxidative phosphorylation and decreased amount of antioxidant defense (catalase, superoxide dismutase and peroxidase) make cardiomyocytes more susceptible to cardiotoxicity compared to other cells. Although doxorubicin is used as one of the anti-cancer anthracycline antibiotics, it has been reported in studies that it causes chronic toxicity in vital organs such as the heart, tissues such as testes and ovaries, and this effect is more common in patients receiving doxorubicin (Altieri et al., 2016). In this study, the pharmacological effect of doxorubicin, an anticancer drug, and its toxicity in the heart and reproductive system were compiled with the information obtained from the literature.
... The ingestion of 3 mg/kg of p-synephrine did not modify cardiovascular variables at rest in the morning or in the evening while the magnitude of side effects was minor and equivalent with placebo and p-synephrine intakes at both times of the day. This investigation provides further evidence to consider p-synephrine as a safe substance, at least for healthy individuals, coinciding with previous reports in both human and animal studies [5,42,43]. However, more investigations are needed in other populations of individuals that may use p-synephrine to enhance fat oxidation during exercise, as most of the reports indicating lack of pernicious effects after p-synephrine intake have been carried out in young and healthy individuals. ...
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 interaction (p = 0.580). In summary, the acute intake of 3 mg/kg of p-synephrine before exercise did not increase MFO and Fatmax, independently of the time of day, in female athletes. This indicates that the time of day is not a factor explaining the lack of effectiveness of this substance to enhance fat oxidation during aerobic exercise in women.
