Synephrine is a naturally occurring chemical that has been sought after by athletes and those looking to lose weight due to its effects on the body’s energy production. However, this compound can also act as an antioxidant and anti-inflammatory agent and may have other important health benefits. Read on to learn more about the benefits, mechanisms, and the safety of synephrine supplementation.
What is Synephrine?
Synephrine is a biogenic amine .
It is found at high levels in the peels of citrus plants, like bitter orange or Seville orange (Citrus aurantium). Extracts from fruits or peels of these plants have been used in traditional Chinese medicine to treat stomach problems and allergies for hundreds of years [2, 3].
There is much confusion over whether synephrine is safe and what effects it has on the body. This is because many sources, and even some scientific journals, confuse synephrine with other substances including:
- Bitter orange (C. aurantium) extract – has high amounts of synephrine but also contains other chemicals [4, 5]
- Phenylephrine/m-synephrine/neo-synephrine – a chemical very close in structure to synephrine (also called p-synephrine) that affects the body differently. M-synephrine is used as a nasal decongestant and also to dilate pupils during eye surgery. While plant sources contain mostly p-synephrine, many supplements do not state which form they contain, and m-synephrine has been found in supplements [6, 7, 8, 9, 10, 11]
- Ephedrine – has a similar chemical structure to synephrine, and has been banned due to health risks. Synephrine has fewer adverse effects on the heart 
Mechanism of Action
Effects on Metabolism
P-synephrine affects the body’s energy production, by altering the function of the liver, which produces many enzymes and plays a large role in regulating digestion and energy production in the body. It:
- Increases the breakdown of glucose and glycogen in the liver of rats and mice [13, 14, 15].
- Prevents the conversion of sugars into fats in mice .
- Increases the amount of ATP available to power chemical reactions in the liver of mice .
- Increases glucose consumption in muscle by stimulating AMPK, an enzyme that senses fuel levels in cells and stimulates burning of fats. It also increases the intake of sugar into cells [16, 17].
- Inhibits α-amylase and α-glucosidase, enzymes that digest complex starches. This is likely to prevent post-meal blood sugar spikes .
P-synephrine only weakly activates alpha-1 and alpha-2 adrenoreceptors, which typically respond to adrenaline (norepinephrine) and increase heart rate and blood pressure.
Ephedrine is similar in structure to synephrine, but it strongly activates the alpha-1 and alpha-2 adrenoreceptors. M-synephrine more strongly activates these adrenoceptors than p-synephrine, but still less than ephedrine or adrenaline [21, 22, 23, 24].
Synephrine stops the production of eotaxin-1, a molecule that signals to eosinophils to move to an inflamed area. It also blocks the activity of the NADPH oxidase, an enzyme produced in neutrophils that creates many reactive oxygen species [27, 28, 29].
However, these effects have not been explored in animal or human studies.
Health Benefits of Synephrine
1) May Increase Metabolic Rate
A study (DB-RCT) of 10 subjects given 50 mg of p-synephrine showed that the subjects burned 65 calories more than participants given placebo in the first 75 minutes after taking the supplement.
Subjects given synephrine did not have increased blood pressure or heart rate .
2) May Aid Fat Loss
Another DB-RCT of 23 people given a combination of caffeine and bitter orange extract (C. aurantium) showed higher amounts of fat being burned even while at rest than those given placebos. This study also found no difference in heart rate or blood pressure between the groups .
These results are supported by a DB-RCT of 12 men that showed increased fat burning at rest and up to 30 minutes after exercise in men given synephrine, or a combination of synephrine and caffeine compared to placebo. In this study, only those men given caffeine showed increased heart rates .
Small doses of caffeine may be needed for synephrine to burn fat while the body is at rest, however. Another study (DB-RCT) of 18 people found that p-synephrine without caffeine did not burn more fat at rest, but did burn more during exercise .
3) May Improve Athletic Performance
A study (DB-RCT) of 12 men showed that p-synephrine taken 45 minutes before exercise increased the number of repetitions and maximum weight load when performing squats compared to placebo.
Taking caffeine in addition to p-synephrine further increased the subjects’ maximal squat repetitions and weight load .
However, another study (RCT) of 13 sprinters given p-synephrine failed to show improvement in sprint velocity or jumping heights compared to placebo .
4) May Treat Stomach Problems Like IBS (Irritable Bowel Syndrome)
No studies directly link synephrine to the relief of stomach problems, but its ability to reduce intestinal muscle movement makes it a promising treatment for these health issues.
5) May Improve Mood and Energy Levels
6) May Be an Antioxidant
Synephrine reduced the production of reactive oxygen species (ROS) released by neutrophils (a type of white blood cell found at sites of inflammation) by inhibiting the enzyme NADPH oxidase, which produces many types of free radicals .
7) May Reduce Inflammation
In cell studies, synephrine stopped the production of eotaxin-1, a molecule that signals to eosinophils to move to an inflamed area.
8) May Reduce Allergy Symptoms
A study performed using guinea pigs showed that synephrine reduced spasms of the smooth muscle in the trachea, a symptom that is associated with coughing. Synephrine also reduced asthma symptoms that occurred when the animals were given histamines .
9) May Be an Antibiotic
One laboratory study showed that synephrine prevented the growth of some bacteria including E. coli, which can cause food poisoning, as well as Staphylococcus aureus, which can cause skin infections .
10) May Treat Fungal Infections
Bitter orange oil, which contains synephrine in addition to other active ingredients, in one study of 60 patients, improved fungal skin infections of the (feet, body/skin, or groin) in 2 to 3 weeks in over 80% of participants [4, 44].
It is sometimes claimed that synephrine may treat fungal skin infections, commonly known as ringworm, but synephrine itself has not been studied as for this use.
Side Effects, Limitations, Drug Interactions & Dosage
Safety and Side Effects
Serious side effects of supplements that contain synephrine have been reported. Most of these reports stem from the use of supplements that contain other active ingredients like caffeine in addition to synephrine, making it impossible to know if synephrine or other ingredients are responsible.
Reported side effects of synephrine-containing supplements include:
- Hallucinations/psychosis 
- Coronary spasms and thrombosis 
- Heart rhythm disturbances (ventricular fibrillation) 
- A decrease in muscle size (rhabdomyolysis) 
- Kidney failure 
- Blood clots 
- Nerve damage due to increased pressure in muscles (bilateral compartment syndrome) 
- Chest pain (variant angina) 
- Stroke 
However, a review of 30 human studies involving over 600 subjects concludes that p‐synephrine (within a bitter orange extract) does not adversely affect the heart, liver, kidneys, or thyroid at doses up to 100 mg. Over 40% of these subjects consumed caffeine in conjunction with bitter orange extract (p‐synephrine) .
Limitations and Caveats
The longest study on the safety of synephrine followed 16 individuals over just 15 days. No adverse effects were reported in this study, but further research is needed to determine if synephrine is safe to consume over longer periods of time .
Higher doses of synephrine may be associated with a higher risk of adverse effects. A study of mice showed high rates of serious side effects, including gasping and reduced motor function.
Caffeine combined with synephrine may be more likely to cause elevated blood pressure and heart rate than synephrine alone, with the risk being even greater when high doses of caffeine were taken (320 mg daily or more) [55, 56].
Synephrine may interact with other supplements and medicine. Known interactions include:
- Caffeine – increases the effect of synephrine on the body’s ability to burn fat but is also associated with greater risk for adverse heart-related effects [37, 55]
- MAOIs (monoamine oxidase inhibitors, used to treat depression) – may cause increased blood pressure when taken with substances similar to synephrine 
- Gliclazide (taken to control diabetes) – may have an increased effect in reducing blood sugar when taken with synephrine 
Natural Sources/Forms of Supplementation
Synephrine occurs naturally in certain species of plants:
- Citrus fruits especially Seville oranges and Satsuma oranges 
- Bitter orange (C. aurantium) peel extracts 
- Evodia rutaecarpa, an herb used in traditional Chinese medicine 
- Pill or supplement, often in combination with other ingredients
Evidence shows that it is safe to consume up to 50 mg per day of synephrine without caffeine. In combination with up to 320 mg of caffeine, it is only recommended to take up to 40 mg of synephrine per day .
- “My appetite decreased and my mood has been enhanced. I feel less fatigued and more energized while using it. I would recommend this to anyone, but I would start out taking only half of the recommended dose or you will not be able to sleep.”
- “Synephrine is only as good as caffeine- it only works for a short time and is followed by a big let down.”
- “After taking it for a couple of weeks I’ve noticeably lost weight. I’m only taking one tablet a day, so I’m sure if I took the recommended dose, my results would be faster. I didn’t have any jitters or weirdness at all.”
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