Synephrine is a naturally occurring chemical that has been sought after by athletes and those looking to lose weight; some people believe that it increases the body’s energy production, but what does the science say? Read on to learn more about the potential benefits, mechanisms, and the safety of synephrine supplementation.
What is Synephrine?
Synephrine is a biogenic amine [1].
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 and controversy 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, which 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, which has a similar chemical structure to synephrine and has been banned due to health risks [12]
Mechanism of Action
Metabolism
Some researchers have argued that P-synephrine may alter the function of the liver, which produces many enzymes and plays a large role in regulating digestion and energy production in the body. In animal and cell studies, it:
- Increased the breakdown of glucose and glycogen in the liver of rats and mice [13, 14, 15].
- Prevented the conversion of sugars into fats in mice [15].
- Increased the amount of ATP available to power chemical reactions in the liver of mice [15].
- Increased glucose consumption in muscle by stimulating AMPK, an enzyme that senses fuel levels in cells and stimulates the burning of fats. It also increases the intake of sugar into cells [16, 17].
- Inhibited α-amylase and α-glucosidase, enzymes that digest complex starches. This is likely to prevent post-meal blood sugar spikes [18].
As a Stimulant
P-synephrine weakly activates alpha-1 and alpha-2 adrenoreceptors, which typically respond to adrenaline (norepinephrine) and increase heart rate and blood pressure. Some researchers have used this result to conclude that p-synephrine is not likely to cause elevations in blood pressure or heart rate [19, 20].
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].
P-synephrine also stimulates neuromedin U2 receptors, molecules found mostly in the hypothalamus, which increases wakefulness [25, 26].
Anti-Inflammatory Activity
In cells, 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].
Synephrine also reduces the activation of NF-κB. Overactive NF-κB plays a role in many inflammatory diseases like asthma, inflammatory bowel disease, and psoriasis [30, 31].
Oxidative Stress
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 [29].
Other Effects
Synephrine may also block acetylcholinesterase and butyrylcholinesterase, enzymes that are harmful in Alzheimer’s disease [18, 32].
However, these effects have not been explored in animal or human studies, and this finding from cell studies may have no clinical relevance whatsoever.
Potential Benefits of Synephrine
Synephrine supplements have not been approved by the FDA for medical use and generally lack solid clinical research. Regulations set manufacturing standards for them but don’t guarantee that they’re safe or effective. Speak with your doctor before supplementing with synephrine.
Possibly Effective For
1) Metabolic Rate & Fat Burning
A study 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 [11].
A study of 17 people given p-synephrine before exercise showed that people given p-synephrine burned more fat as opposed to carbohydrates during exercise. No effect on heart rate was observed [10].
Another study 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 [33].
These results are supported by a study 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 [34].
Small doses of caffeine may be needed for synephrine to burn fat while the body is at rest, however. Another study of 18 people found that p-synephrine without caffeine did not burn more fat at rest, but did burn more during exercise [35].
The sizes of these studies are small, so more research is needed to confirm these effects. More research is also required to fully clarify the relative role of synephrine in studies on bitter orange or combinations with caffeine [12, 36].
Insufficient Evidence For
While some clinical evidence has emerged for the potential benefits in this section, the available studies are too small, contradicted by other studies, or yet to be repeated. As such, the evidence is insufficient to recommend synephrine for these purposes, and there are better-studied alternatives available.
2) Athletic Performance
In a study of 12 men, 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 [37].
However, another study of 13 sprinters given p-synephrine failed to show improvement in sprint velocity or jumping heights compared to placebo [38].
3) Antifungal Activity
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, 39].
Animal and Cell Studies (Lacking Evidence)
No clinical evidence supports the use of synephrine for any of the conditions listed in this section. Below is a summary of the existing animal and cell-based research, which should guide further investigational efforts. However, the studies listed below should not be interpreted as supportive of any health benefit.
4) Irritable Bowel Syndrome
Synephrine reduced the movement of intestinal muscles in animals. Overactive intestinal muscles are linked to a number of stomach problems, like irritable bowel syndrome and constipation [2, 40].
No studies directly link synephrine to the relief of stomach problems, but its ability to reduce intestinal muscle movement makes it a promising avenue of future research for these health issues.
5) Mood and Energy
Mice with classic signs of depression, including sleep problems and changes in eating habits, do worse in response to stressful events, like being forced to swim, than healthy mice do.
One study showed that mice fed synephrine were able to swim longer, indicating higher energy and mood levels [41, 42, 43].
6) Inflammation
In mice with lung injury, synephrine reduced the number of inflammatory cells and inflammatory cytokines TNF-alpha and IL-6, while increasing the anti-inflammatory IL-10 [30].
In addition, synephrine also reduced the activation of NF-κB. Overactive NF-κB plays a role in many inflammatory diseases like asthma, inflammatory bowel disease, and psoriasis [30, 31].
In cell studies, synephrine stopped the production of eotaxin-1, a molecule that signals to eosinophils to move to an inflamed area.
It also blocked the activity of the NADPH oxidase, an enzyme produced in neutrophils that creates many reactive oxygen species [27, 28, 29].
7) 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 [3].
8) Antimicrobial Activity
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 [44].
Side Effects & Precautions
Serious side effects of supplements that contain synephrine have been reported. In many cases, these were reported for supplements that contain other active ingredients like caffeine in addition to synephrine. In order to avoid adverse effects or unexpected interactions, talk to your doctor before using synephrine.
Reported side effects of synephrine-containing supplements include:
- Hallucinations/psychosis [45]
- Coronary spasms and thrombosis [46]
- Heart rhythm disturbances (ventricular fibrillation) [47]
- A decrease in muscle size (rhabdomyolysis) [48]
- Kidney failure [48]
- Blood clots [48]
- Nerve damage due to increased pressure in muscles (bilateral compartment syndrome) [48]
- Chest pain (variant angina) [49]
- Stroke [50]
A review of 30 human studies involving over 600 subjects concluded that p‐synephrine (within a bitter orange extract) did not adversely affect the heart, liver, kidneys, or thyroid at doses of up to 100 mg. Over 40% of these subjects consumed caffeine in conjunction with bitter orange extract (which contains p‐synephrine) [20].
Higher doses of synephrine have also produced worse adverse effects in safety studies. A study of mice showed high rates of serious side effects, including gasping and reduced motor function. The study used very high doses of synephrine: 150 to 2,000 mg/kg of body mass, compared to the recommended dose of 2 mg/kg body mass or less [51, 20].
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) [52, 53].
Further, in studies in mice both bitter orange (C. aurantium) extract and caffeine increase blood pressure, while pure synephrine had minimal effects on heart rate and blood pressure [54, 55].
If you take synephrine and experience cardiac symptoms, seek medical attention immediately. Your doctor can determine whether medical intervention is necessary.
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 [56].
Drug Interactions
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, 52]
- MAOIs (monoamine oxidase inhibitors, used to treat depression): may cause increased blood pressure when taken with substances similar to synephrine [57]
- Gliclazide (taken to control diabetes): may have an increased effect in reducing blood sugar when taken with synephrine [58]
Sources and Supplementation
Synephrine occurs naturally in certain species of plants:
- Citrus fruits especially Seville oranges and Satsuma oranges [59]
- Bitter orange (C. aurantium) peel extracts [60]
- Evodia rutaecarpa, an herb used in traditional Chinese medicine [29]
Synephrine is also available as a supplement, often in combination with other ingredients.
Dosage
There is no safe and effective dose of synephrine because no sufficiently powered study has been conducted to find one. Furthermore, the FDA has not approved synephrine for any medical purpose or health claim. However, some small clinical studies have found beneficial effects associated with certain amounts of supplemental synephrine.
In clinical trials, 50 mg per day of synephrine did not produce adverse effects when taken without caffeine. In combination with up to 320 mg of caffeine, the studies did not use more than 40 mg of synephrine per day [20].
