Synephrine has been used to promote weight loss; however, its safety and efficacy have not been fully established. This article aims to provide a comprehensive overview of synephrine, its potential benefits, side effects, and its debated role in weight loss and athletic performance.
What is Synephrine?
Synephrine is a naturally occurring protoalkaloid found in Citrus aurantium, also known as bitter orange. Bitter orange is a fruit-bearing tree native to Asia. In traditional Chinese medicine, the peel and/or whole dried immature fruit of C. aurantium (BO) is used for a variety of health applications, including indigestion, diarrhea, dysentery, and constipation, and as an expectorant. BO has been used in South American folk medicine to treat insomnia, anxiety, and epilepsy.
Synephrine exists in three different positional isomeric forms: ortho, meta, and para. It is generally accepted that only para-synephrine (p-synephrine) can be found in bitter orange fruits. 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). Ortho-synephrine (o-synephrine) is not used as a pharmaceutical substance, and its natural occurrence has not been documented.
The average synephrine content of the dried fruit extracts of Citrus aurantium has been reported to be between 3% and 6%.
Synephrine vs. Ephedrine
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. 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. The use of ephedrine is associated with the increased risk of myocardial infarction, hypertension, and stroke, but such pronounced effects on the cardiovascular system are not expected when using p-synephrine.
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Uses of Synephrine
Synephrine is used in pre-workout supplements to improve performance and to promote weight loss since it has thermogenic and sympathomimetic properties. Bitter orange extract (BOE) has been widely used for ~20 years as the patented, standardized aqueous/ethanol extract of the dried immature fruit. P-synephrine constitutes ~90% of the protoalkaloids in BOE and to which extracts are standardized.
Synephrine was added to the Monitoring Program in Competitions of the World Anti-Doping Agency, but it is not yet considered as a prohibited substance (WADA) in 2022.
Synephrine and Weight Loss
The global increase in obesity is strongly connected to modifiable lifestyle factors, including sedentary lifestyle and diet. Obesity is associated with serious health problems and related comorbidities, and even modest weight loss can result in improved systolic and diastolic blood pressure and blood cholesterol levels. 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. 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.
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.
Meta-Analysis of Synephrine's Efficacy
A meta-analysis was conducted to systematically evaluate synephrine's efficacy regarding weight loss and to assess its safety, focusing on its cardiovascular side effects. 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.
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Altogether, 18 articles were included in the meta-analysis. 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, there is no evidence that synephrine can facilitate weight loss.
Synephrine and Fat Oxidation during Exercise
Some investigations have aimed to determine the efficacy of p-synephrine to enhance fat utilization 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 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.
Mechanisms of Action
The purported effects of p-synephrine to enhance thermogenesis and fat oxidation at rest and during exercise were based on its structural similarity with endogenous amine neurotransmitters such as epinephrine and norepinephrine. Due to this structure, p-synephrine has the ability to bind β-3 adrenoceptors. As a result, p-synephrine increases lipolysis at rest, although the evidence of enhanced lipolysis during exercise is lacking.
On the other hand, p-synephrine has a low binding affinity for α- and β-1 and β-2 adrenoreceptors. Furthermore, p-synephrine can stimulate specific receptors in the brain. The p-synephrine is a highly potent and selective agonist of Neuromedin U2 receptors (NMU2R). Specifically, NMU2R is prominent in the hypothalamic regions and is known to be associated with regulation of several important physiological functions, including food intake, energy balance, stress response, and nociception.
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In experiments carried out with animals, in which the isolated rat liver was perfused in vivo after oral administration of p-synephrine, it has been found that p-synephrine has a potent capacity to inhibit the pyruvate dehydrogenase enzyme. Lastly, p-synephrine suppresses the 3T3-L1 cell adipogenesis by reducing the expression level of CCAAT-enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ), which subsequently leads to a reduction in the fatty acid-binding protein 4 (aP2) expression.
Synephrine and Athletic Performance
Despite the structural similarity of p-synephrine with endogenous amine neurotransmitters, the evidence is pointing toward the lack of ergogenic activity of p-synephrine during exercise and sport, although studies to demonstrate an increased exercise capacity after acute p-synephrine intake are scarce and contradictory. The acute intake of p-synephrine (3 mg/kg of body mass) did not change running performance during 60-m and 100-m sprint races and it did not affect single and repeated jumping capacity of sprinters when compared to a placebo. In addition, the ingestion of the same dose of p-synephrine did not increase peak wattage nor the maximum oxygen uptake (VO2max) obtained during a ramp exercise test in elite cyclists.
Safety and Side Effects
Currently, there is little if any basis for making definitive statements about the safety of bitter orange extracts or synephrine used in food supplements. Because of its known sympathomimetic properties and adrenergic effects on the cardiovascular system, the use of synephrine in food supplements is debated. Even though there is no legislation which limits the content of synephrine and other alkaloids in dietary supplements, based on the Directive 2002/46/EC, each country is supposed to set a maximum level of synephrine.
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; however, the prevalence is not known.
Meta-Analysis Findings on Cardiovascular Effects
The meta-analysis mentioned earlier found that 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). This suggests that synephrine tends to raise blood pressure and heart rate.
ANSES Recommendations
The French food safety authority (ANSES) concluded in its assessment on synephrine 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).
Other Potential Side Effects
Other side effects included complaints of headaches, hyperventilation, racing HR, feelings of dizziness, and feelings of irritability or perspiration, palpitations, shortness of breath, nervousness, and blurred vision.
Synephrine and Caffeine
Bitter orange contains many chemicals that affect the nervous system. These chemicals might cause heart problems in healthy adults. Bitter orange, taken by itself or with stimulants such as caffeine or caffeine-containing herbs, might increase the risk for high blood pressure, fainting, heart attack, stroke, and other serious side effects.
P-Synephrine is regarded as a nonstimulant thermogenic agent, due to its lack of effects on the cardiovascular system, while caffeine is a stimulant thermogenic. The two exhibit different mechanisms of action, and p-synephrine as BOE is frequently combined with caffeine in dietary supplements.
Studies on Synephrine and Caffeine Combinations
Several studies have been conducted to assess the safety of BO (C. aurantium) extract (p-synephrine) and caffeine in combination. Human studies involving p-synephrine and caffeine have shown that commonly consumed doses of p-synephrine do not produce significant adverse effects and are free of stimulant activity.
Health Canada concluded that the use of up to 50 mg/day of p-synephrine alone in healthy adults “is not likely to cause any adverse health consequences”. A similar conclusion was drawn with respect to products containing ≤40 mg of p-synephrine when combined with ≤320 mg/day of caffeine.
Intertek Scientific and Regulatory Consultancy stated that dosages “not likely to cause adverse effects” included 70 mg p-synephrine alone or 40 mg in combination with 320 mg of caffeine. Furthermore, if taken as divided doses spaced out over the course of the day, 100 mg p-synephrine alone or 70 mg p-synephrine in combination with 400 mg caffeine is unlikely to be associated with adverse health effects.
The European Food Safety Authority (EFSA) has published a scientific opinion on the safety of caffeine, stating that “single doses of caffeine up to 200 mg (about 3 mg/kg body weight for a 70 kg adult) do not give rise to safety concerns”.
Case Studies
Some case studies have raised concerns about the safety of synephrine and caffeine combinations, but these studies often lack detailed information about the composition of the products being taken, the amounts of the various ingredients, and the conditions under which the supplements were being taken.
Animal Studies
Several animal studies have been conducted by the National Center for Toxicological Research in conjunction with the FDA regarding the safety of BOE and p-synephrine. In a study that examined the developmental toxicity of C. aurantium in rats, the authors concluded that doses of up to 100 mg p-synephrine/kg body weight did not produce developmental toxicity.
Interactions with Medications
Bitter orange might interact with several medications:
- Indinavir: Bitter orange might decrease how quickly the liver breaks down indinavir, potentially increasing its effects and side effects.
- Medications broken down by the liver: Bitter orange might change how quickly the liver breaks down these medications, altering their effects and side effects.
- MAOIs: Bitter orange contains chemicals that stimulate the body. Some medications used for depression can increase these chemicals, potentially leading to adverse effects.
- Medications that affect the heart: Bitter orange might affect electrical currents in the heart, increasing the risk of irregular heartbeat.
- Midazolam: Bitter orange can decrease how quickly the body breaks down midazolam, potentially increasing its effects and side effects.
- Stimulants: Bitter orange is a stimulant, and taking it with other stimulants like caffeine can increase blood pressure and heart rate, potentially leading to serious adverse effects.
- Diabetes medications: Bitter orange might lower blood sugar levels, and taking it with diabetes medications might cause blood sugar to drop too low.
- Colchicine: Bitter orange might affect levels of colchicine, potentially reducing its benefits or increasing its side effects.
- Sildenafil: Bitter orange can decrease how quickly the body breaks down sildenafil, potentially increasing its effects and side effects.
Dosage and Availability
Bitter orange is available in supplements and topical oils. Supplements containing bitter orange are often marketed for athletic performance and weight loss. The active chemical in bitter orange, synephrine, can cause serious side effects, and products containing this ingredient have been shown to contain amounts much higher than what is listed on the product label. They've also been found to contain many other synthetic stimulants that are banned in supplements.
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.
Methylsynephrine
Methylsynephrine is a chemical that is made in the lab and found in some dietary supplements. According to the US Food and Drug Administration (FDA), methylsynephrine does not meet the definition of a dietary supplement. Also, it is banned by the World Anti-Doping Agency (WADA) for use during competitive sports, and by the Department of Defense (DOD) for use by military personnel.
Methylsynephrine is commonly used for weight loss, athletic performance, lung problems, and other uses, but there is no good scientific evidence to support these uses. Methylsynephrine is a chemical that stimulates the heart. It might increase blood pressure and heart rate. It might also increase how much blood is pumped around the body.
Due to its potential side effects, it is POSSIBLY UNSAFE. Do not take products with methylsynephrine on the label.