Thermogenic fat burners are certainly the most popular supplement group. These complex products consist out of several substances. Among the most popular thermogenic ingredients is Synephrine, also called ephedrine analog. Although it might be popular alongside ephedrine, having a similar structure and action, Synephrine is far from being the most powerful fat burning agent.
What is Synephrine?
Synephrine is a natural substance found in the bitter orange fruit, also known as Citrus aurantium. Bitter orange is the traditional fruit in folk Chinese medicine. There are many different varieties of this type of fruit that are grown specifically for different purposes. While some may be used in perfumes, the versatility of the extract means that it has numerous functions including the use of it as a flavoring agent, a solvent in Chinese herbal medicine and, most importantly, as an aid for weight loss (1).
The bitter orange fruit has the highest natural content of Synephrine known to man. The standard bitter orange extract contains a concentration of 7% Synephrine. It is also found in other citrus fruits, but its concentrations are significantly lower.
P-Synephrine is the natural form of Synephrine, which should be distinguished from synthetic m-synephrine (neosynephrine, methyl synephrine). It has the identical structure of ephedrine and is also chemically very similar to other substances that have the structure of phenylethylamine, although they also have many differences.
Changing the n-methyl group of Synephrine with a hydrogen atom forms octopamine, and the change of the beta-hydroxy group forms n-methylamine (2).
How Does Synephrine Work?
This ingredient can be successfully synthesized in the human body. Animal studies have shown that Synephrine occurs in the brain. Synephrine itself appears to be a residual product of the tyramine metabolism. Thiamine is metabolized into octopamine, which in turn is oxidized into Synephrine. The oxidation of octopamine in Synephrine, as well as the oxidation of Synephrine itself, is accomplished by MAO enzymes, with MAO-A being more active (3) (4).
Most properties of this ingredient are related to its agonist (stimulator) function of the adrenoreceptors, preferably the alpha-1 receptor to alpha-2, requiring relatively high doses to activate them. It can also act on beta-receptors but in a significantly weaker fashion. Adrenoreceptors are associated with the stimulation of the sympathetic nervous system that mobilizes the energy for the whole body. The alpha-1 receptor is responsible for muscle contractions, vasoconstriction, liver and fat tissue glycogenesis, and stimulation of sweating (5).
There is also evidence that Synephrine has a partial effect on serotonin receptors, which are directly correlated to good mood (6).
Following oral administration of Synephrine, peak plasma concentrations occur within 1-2 hours and the half-life of the substance is about 2 hours. It has been concluded that the intake of 150mg of Synephrine drastically increases octopamine levels in the urine, which exceeds the allowance for doping control. So if you’re a professional athlete, you might want to reconsider taking Synephrine containing supplements (7).Proven and Potential Synephrine
Benefits of Synephrine
- Synephrine intake strengthens the metabolism and widens calorie expenditure. The use of 50mg of Synephrine without physical activity increases calorie consumption without any side effects. This action of Synephrine is due to its ability to simulate alpha-1 and alpha-2 receptors.
- Synephrine is a thermogenic compound, however, studies done on this topic are still inconclusive. Right now there is only one study that links that positive effects of bitter orange on thermogenesis (8).
- Synephrine stimulates alpha-receptors, directly impacting the sympathetic nervous system. This leads to an increase in energy, stamina, concentration, and cognition. However, these effects can be expected only with relatively high doses of Synephrine (9).
- Synephrine has potential anti-estrogen properties. Synephrine targets the adrenal gland mass, which may be due to the alpha-1 receptor activity which enhances vasoconstriction and reduces fluid in organs. The effect of Synephrine is relatively moderate, with ephedrine showing statically a greater change (10).
The Recommended Dose
The recommended daily dose of Synephrine is between 10-20mg, up to 3 times a day. In some cases, athletes used a dose of 50mg for the best workout stimulation and fat loss. However, high doses such as the 50mg one are only recommended once per day.
Synephrine Side Effects
Synephrine has been widely speculated to increase blood pressure. However, taking p-synephrine does not technically lead to an increase in blood pressure, whereas the intake of bitter orange fruit does bring a spike in blood pressure. Also, different extracts show different results, with a lower content extract leading to an increase in blood pressure, while the patented Advantra-Z (30% Synephrine) has virtually no impact on it. Although all extract leads to an increase in heart rhythm.
P-synephrine (natural form) shows no side effects and is safe for consumption. It is possible however that methyl synephrine induces toxicity. Animal tests indicate that a dose of 400-500mg/kg body weight is highly toxic, while a lower dose over a prolonged period of time showed less toxic effects (11).
High concentrations of Synephrine, such as the tyramine metabolite, are associated with the onset of severe headaches and migraines. Migraine individuals have been found to have greater amounts of Synephrine in their blood plasma. Although theoretically, oral intake of Synephrine may worsen their conditions (12).
A high dose of Synephrine may lead to a positive doping result. Taking 150mg of Synephrine boosts the release of octopamine into the urine, which is banned. On the other hand, 54mg of Synephrine (900mg of extract) was found to result in a positive doping test.
It is not recommended to supplement with Synephrine if pregnant since it may cause contractions. Individuals who suffer from arrhythmia or glaucoma should also avoid Synephrine as it may aggravate their conditions.
Synephrine and Other Stimulants
In order to stimulate the nervous system, Synephrine is successfully combined with caffeine, and these two stimulants together show synergistic properties. Other suitable synergists are yohimbine, phenylethylamine, and evodia.
For fat burning, Synephrine successfully combines with green tea, caffeine, yohimbine, forskolin, and others.
Synephrine has a positive effect on the metabolism by stimulating the consumption of calories. The addition of bioflavonoids enhances the effects of Synephrine. With 600mg of Naringin added, the consumption of calories is increased to 129, and with an additional 100mg of hesperidin, the value reaches 183 calories.
It is not recommended to combine Synephrine with antidepressants!
It’s clear that Synephrine, a chemical found in bitter orange or citrus aurantium, can help with weight management and does have some benefits. However, this compound appears to be most effective for weight loss and athletic performance when combined with other stimulants such as caffeine and yohimbine.
Synephrine is also linked to a variety of potential adverse effects, so it’s best to fully understand the supplement and all of its abilities before deciding to supplement it. It’s also crucial to avoid very high doses of this compound. However, this is an issue since most supplement brands formulate their ingredients in the form of a proprietary blend.
If you suffer from any pre-existing medical conditions or health issues, be sure to consult your physician before taking any supplements that contain Synephrine.
- Sidney J. Stohs. “Safety, Efficacy, and Mechanistic Studies Regarding Citrus aurantium (Bitter Orange) Extract and p‐Synephrine.” Phytother Res. (2017 Oct). Viewed at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655712/
- John E. Thomas, Jamalah A. Munir, Peter Z. McIntyre, and Michael A. Ferguson. “STEMI in a 24-Year-Old Man after Use of a Synephrine-Containing Dietary Supplement.” Tex Heart Inst J. (2009).
Viewed at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2801940/
- Brown CM, McGrath JC, Midgley JM, Muir AG, O'Brien JW, Thonoor CM, Williams CM, Wilson VG. “Activities of octopamine and synephrine stereoisomers on alpha-adrenoceptors.” Br J Pharmacol. (1988 Feb). Viewed at:
- Shawky E. “Determination of synephrine and octopamine in bitter orange peel by HPTLC with densitometry.” J Chromatogr Sci. (2014 Sep). Viewed at: https://www.ncbi.nlm.nih.gov/pubmed/23912767
- Ma G, Bavadekar SA, Schaneberg BT, Khan IA, Feller DR. “Effects of synephrine and beta-phenethylamine on human alpha-adrenoceptor subtypes.” Planta Med. (2010 Jul). Viewed at:
- Hibino T, Yuzurihara M, Kase Y, Takeda A. “Synephrine, a component of Evodiae Fructus, constricts isolated rat aorta via adrenergic and serotonergic receptors.” J Pharmacol Sci. (2009 Sep). Viewed at:
- Thevis M, Koch A, Sigmund G, Thomas A, Schänzer W. “Analysis of octopamine in human doping control samples.” Thevis M, et al. Biomed Chromatogr. (2012). Viewed at:
- Jay R Hoffman, Jie Kang, Nicholas A Ratamess, Stefanie L Rashti, Christopher P Tranchina, and Avery D Faigenbaum. “Thermogenic effect of an acute ingestion of a weight loss supplement.” J Int Soc Sports Nutr. (2009). Viewed at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2621121/
- Arbo MD, Franco MT, Larentis ER, Garcia SC, Sebben VC, Leal MB, Dallegrave E, Limberger RP. “Screening for in vivo (anti)estrogenic activity of ephedrine and p-synephrine and their natural sources Ephedra sinica Stapf. (Ephedraceae) and Citrus aurantium L. (Rutaceae) in rats.” Arch Toxicol. (2009 Jan). Viewed at:
- Nam Hee Kim, Ngoc Bich Pham, Ronald J. Quinn, Joong Sup Shim, Hee Cho, Sung Min Cho, Sung Wook Park, Jeong Hun Kim, Seung Hyeok Seok, Jong-Won Oh, and Ho Jeong Kwon. “The Small Molecule R-(-)-β-O-Methylsynephrine Binds to Nucleoporin 153 kDa and Inhibits Angiogenesis.” Int J Biol Sci. (2015).
Viewed at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4515819/
- Stohs SJ1, Preuss HG, Shara M. “The safety of Citrus aurantium (bitter orange) and its primary protoalkaloid p-synephrine.” Phytother Res. (2011 Oct). Viewed at: https://www.ncbi.nlm.nih.gov/pubmed/21480414
- Schmitt GC1, Arbo MD, Lorensi AL, Maciel ES, Krahn CL, Mariotti KC, Dallegrave E, Leal MB, Limberger RP. “Toxicological effects of a mixture used in weight loss products: p-synephrine associated with ephedrine, salicin, and caffeine.” Int J Toxicol. (2012 Mar). Viewed at: https://www.ncbi.nlm.nih.gov/pubmed/22408069