Synephrine

Synephrine

1. Identity: Chemical and Botanical Profile

1.1 Names and Classification

Synephrine is a sympathomimetic phenylethylamine derivative that occurs naturally in citrus fruits. Its systematic chemical name is (R)-4-[1-hydroxy-2-(methylamino)ethyl]phenol; it is also known in the pharmacological literature by the International Nonproprietary Name oxedrine, and in some older references as p-synephrine or Sympatol. Its molecular structure is based on a phenethylamine skeleton and is related to those of many other drugs and to the major neurotransmitters epinephrine and norepinephrine.

Synephrine can exist in three different positional isomeric forms — ortho (o-), meta (m-), and para (p-) — and each positional isomer can also be found in two enantiomeric forms. This distinction is pharmacologically consequential: if the synephrine phenolic 4-OH group is shifted to the meta- or 3-position on the benzene ring, the compound known as phenylephrine (or m-synephrine, or "Neo-synephrine") results. The majority of authors state that only p-synephrine is found in Citrus aurantium (CA) fruits, although some others have claimed that m-synephrine is also present. o-Synephrine cannot be obtained from natural sources. CA fruits contain only the R-(−) enantiomeric form.

There is an important distinction between studies concerning synephrine as a single chemical entity — noting that synephrine can exist as either of two stereoisomers, d- and l-synephrine, which are chemically and pharmacologically distinct — and synephrine mixed with other drugs or botanical extracts in a supplement, as well as synephrine present as only one chemical component in a naturally-occurring mixture of phytochemicals such as the rind or fruit of a bitter orange. Mixtures containing synephrine as only one of their chemical components should not be assumed to produce exactly the same biological effects as synephrine alone.

In physical appearance, synephrine is a colorless, crystalline solid and is water-soluble. As a synthetic drug, synephrine first appeared in Europe in the late 1920s, under the name of Sympatol.

1.2 Botanical Sources

p-Synephrine is the most active substance in Citrus aurantium (CA), the major natural source for the dietary supplements industry. CA is a tree from the Rutaceae family, popularly named Bitter Orange, Seville Orange, Sour Orange, Green Orange, Zhi Shi, and Kijitsu. Synephrine is found in the fruits of several trees from the Rutaceae family, including bitter orange (Citrus aurantium), and from some other citrus species such as varieties of tangerines "Nova" (Citrus deliciosa "Nova") and Marr's Early sweet orange (Citrus sinensis). The presence of synephrine is also described in other Citrus species, including C. reticulata, C. sinensis, C. deliciosa, C. limon, C. limonia, and C. unshiu, as well as in Evodia rutaecarpa.

The primary pharmacologically active protoalkaloid in bitter orange peel and its extracts is p-synephrine, which comprises greater than 85% of the total protoalkaloids. Other minor protoalkaloidal constituents include octopamine, hordenine, tyramine, and N-methyltyramine; octopamine is present in trace amounts or absent in bitter orange extracts. Synephrine is the main component in fruits (0.10–0.35%) and in dry extracts (3.00–3.08%) and was present in the range 0.25–0.99% in herbal medicines.

1.3 Common Forms and Preparations

Bitter orange extracts are aqueous/ethanolic extracts of the dried immature fruits of C. aurantium that are harvested in May and June. In China, the immature fruits of bitter orange are also known as Fructus aurantii immaturus. Many Citrus aurantium products are made from the juice and concentrated extracts of the peel and are said to contain a fixed percentage of synephrine or total amines. Some dietary supplements, sold for the purposes of promoting weight-loss or providing energy, contain synephrine as one of several constituents; the synephrine is usually present as a natural component of Citrus aurantium, bound up in the plant matrix, but it could also be of synthetic origin, or a purified phytochemical extracted from a plant source and purified to chemical homogeneity. The concentration range found in five different supplements purchased in the US was approximately 5–14 mg/g.

Synephrine is often added to dietary supplements intended for weight loss and enhancement of sports performance, typically in the form of Citrus aurantium extracts and in many cases in combination with caffeine. In recent years, synthetic p-synephrine has also been marketed as an alternative to the naturally occurring Citrus-derived p-synephrine.

2. Traditional and Historical Use

2.1 Traditional Chinese Medicine

In traditional Chinese medicine, the peel and/or whole dried immature fruit of C. aurantium has been used for hundreds of years for a variety of health applications, including indigestion, diarrhea and dysentery, constipation, and as an expectorant. C. aurantium extract is widely known as bitter orange extract, derived from the immature (green) fruits of the Seville orange, and is also known as "Chih-shi" or "Zhi shi" in traditional Chinese medicine.

Synephrine had been widely used in traditional Chinese medicine as an energy stimulant due to its beneficial effects on cellular energetics. The dried immature fruit (Zhi Shi or Fructus Aurantii Immaturus) and the slightly more mature fruit (Zhi Qiao or Fructus Aurantii) were both used, with differing emphasis: Zhi Shi was traditionally regarded as more potent in moving qi and breaking up accumulations.

2.2 South American Folk Medicine

Bitter orange has been used in South American folk medicine to treat insomnia, anxiety, and epilepsy.

2.3 Persian and European Traditions

In traditional Persian medicine, bitter orange peel and its blossom hydrosol are used as neuroprotective and antidepressant agents. Bitter orange is also known as Seville orange because it has been grown in Seville, Spain, for over 800 years, where it is used in various food products including marmalades, syrups, and juices that are widely distributed and consumed.

2.4 Ayurvedic and General Traditional Use

The juice, peel, and essential oil have been utilized in traditional medicine systems like Chinese and Ayurvedic practices, where bitter orange was traditionally used to address digestive issues, fatigue, insomnia, and infections. Additional traditional uses include epilepsy, respiratory problems, and skin problems.

2.5 Transition to Modern Supplement Use

p-Synephrine became popular as an active ingredient for thermogenics and weight-loss supplements following the ban of Ephedra species by the U.S. Food and Drug Administration in 2004. Several dietary supplement companies substituted Ephedra with Citrus aurantium or p-synephrine because they purportedly have the capacity to increase the metabolic rate at rest and enhance lipolysis. Bitter orange extracts have been used as dietary supplements for approximately 20 years for weight management, energy production, and sports performance, as well as appetite control.

3. Key Constituents and Active Compounds

3.1 Phytochemical Profile of Citrus aurantium

The most important biologically active constituents of the C. aurantium fruits are phenethylamine alkaloids — specifically octopamine, synephrine, tyramine, N-methyltyramine, and hordenine. The alkaloids p-synephrine and, to a lesser extent, octopamine are believed to be the most active components of C. aurantium. However, the peels of the fruits also contain terpenes, furocoumarins, and flavonoids, including hesperidin, neohesperidin, naringin, and tangaretin.

Flavanones present include neoeriocitrin, narirutin, naringin, hesperidin, neohesperidin, naringenin, and hesperetin. C. aurantium fruits and derivatives contain mainly glycosylated flavanones; in particular, naringin and neohesperidin were found to be the major flavonoids, with concentrations ranging from 1.80 to 26.30 and from 3.90 to 14.71 mg/g, respectively.

3.2 Biosynthesis

Wheaton and Stewart have speculated that the biosynthesis of synephrine in plants could follow the biosynthetic pathway tyramine → N-methyltyramine → synephrine, rather than the tyramine → octopamine → synephrine pathway. Synephrine is also found in the human organism, where it is considered a trace amine due to its low plasmatic levels.

3.3 Structural Relationships to Other Compounds

Replacement of the N-methyl group in synephrine with a hydrogen atom gives octopamine; replacement of the β-hydroxy group in synephrine with a hydrogen atom gives N-methyltyramine. Addition of another phenolic –OH group to the 3-position of the benzene ring produces the neurotransmitter epinephrine; addition of a methyl group to the α-position in the side-chain of synephrine gives oxilofrine (methylsynephrine). These structural relationships explain both the overlapping pharmacology and the important quantitative differences in potency between these compounds.

4. Mechanisms of Action

4.1 Adrenergic Receptor Interactions

p-Synephrine binds to the β-1 and β-2 adrenergic receptors approximately 10,000-fold or less actively than norepinephrine, as demonstrated in guinea pig atria and trachea. This markedly weaker binding to classical β-adrenergic receptors distinguishes p-synephrine from structurally related compounds such as ephedrine.

At the α_1A-adrenergic receptor, synephrine acts as a partial agonist, while both synephrine and β-phenethylamine may act as antagonists of pre-synaptic α_2A/2C-adrenergic receptors present in nerve terminals. Functional studies on the α_1A-AR subtype showed that synephrine was a partial agonist giving a maximal response at 100 μM that was equal to 55.3% of the L-phenylephrine maximum.

4.2 β-3 Adrenergic Receptor and Lipolysis

Research examining the lipolytic activity of potential β-3 adrenergic receptor agonists including p-synephrine and p-octopamine in white fat cells from hamsters, rats, dogs, humans, and guinea pigs found that p-octopamine was the most selective for β-3 adrenergic receptors. p-Octopamine was the only amine studied that fully stimulated lipolysis in rat, hamster, and dog fat cells, but was ineffective in human and guinea pig fat cells. p-Synephrine was partially active in stimulating lipolysis in all species, while tyramine, dopamine, and β-phenylethylamine exhibited no activity.

Furthermore, p-synephrine was unable to block α-2 adrenoreceptors and did not provoke noticeable stimulation of glucose transport. These results strongly suggest, but do not prove, the involvement of β-3 adrenoreceptors. It can be concluded that, with respect to bitter orange extracts, the higher the amount of p-synephrine and the lower the amounts of tyramine and N-methyltyramine, the greater the lipolytic activity.

4.3 cAMP/PKA Signaling Pathway

Analysis of the chemical structure and pharmacological action of synephrine indicates that its molecular action involves interference with the 3′,5′-cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) signaling. This pathway is triggered by sympathetic activation to restore cellular homeostasis via stimulating glucose uptake, lipolysis, fatty acid oxidation, mitochondrial biogenesis, and cell proliferation.

4.4 Comparison with Ephedrine

Human, clinical, animal, and in vitro studies indicate that p-synephrine does not act as a cardiovascular stimulant at commonly used doses, nor does it augment the cardiovascular effects of caffeine. This lack of cardiovascular stimulation by p-synephrine can be readily explained by its poor adrenergic receptor binding and lack of indirect adrenergic effects. In contrast, ephedrine causes substantial stimulation of β-1, β-2, and α-1 adrenergic receptors and also acts indirectly by promoting norepinephrine release — mechanisms that are largely absent for p-synephrine at typical doses.

5. Scientific Evidence by Area of Use

5.1 Weight Management and Thermogenesis

Overview of Clinical Evidence

A review summarized the published as well as unpublished human studies involving Citrus aurantium extract and its primary protoalkaloid p-synephrine, encompassing the results of over 20 studies involving a total of approximately 360 subjects who consumed p-synephrine alone or in combination with other ingredients. Over 50% of subjects involved were overweight or obese, and approximately two-thirds of these overweight/obese subjects consumed caffeine (132–528 mg/day) in conjunction with p-synephrine (10–53 mg/day). Bitter orange/p-synephrine-containing products were consumed for up to 12 weeks. Approximately 44% of subjects consumed a bitter orange/p-synephrine-only product, while the remainder consumed a complex product containing multiple ingredients in addition to p-synephrine.

Resting Metabolic Rate

One randomized, placebo-controlled, double-blind study examined the effect of 50 mg p-synephrine (Advantra Z®, 60% p-synephrine) alone or in combination with selected flavonoids in 40 human subjects on resting metabolic rate. The amount of p-synephrine in the product was verified by independent analysis. At 75 minutes after consumption, a 6.9% increase in resting metabolic rate was observed in response to p-synephrine relative to the placebo-control group. No significant effects were observed with respect to blood pressure or heart rate, nor were there any significant differences on a 10-item self-report questionnaire addressing nervousness, tension, anxiety, hunger, energy, headache, general discomfort, and sleepiness.

Meta-Analytic Findings on Weight Loss

A systematic review and meta-analysis of placebo-controlled human clinical trials with synephrine intervention was reported according to PRISMA guidelines using the PICOS format and following CONSORT recommendations. Altogether, 18 articles were included. Both systolic and diastolic blood pressure 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). 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, synephrine tends to raise blood pressure and heart rate, and there is no evidence that synephrine can facilitate weight loss. Further studies are needed to confirm evidence of its safety and efficacy.

It is believed that, in the long term, chronic ingestion of p-synephrine may reduce fat mass through increased thermogenesis and fat oxidation, although there is no clinical or research evidence to support this notion using supplements containing only synephrine.

Evidence strength assessment: The available clinical evidence does not support weight loss as an efficacy endpoint for p-synephrine, whether administered alone or in combination products. Meta-analysis demonstrates that synephrine does not produce significant changes in body weight or body composition. Studies are limited by small sample sizes, short durations, variable product formulations, and frequent co-administration of caffeine and other agents, making it difficult to attribute any observed effects to synephrine alone.

5.2 Exercise Performance and Fat Oxidation During Exercise

In a double-blind, randomized, and counterbalanced experimental design, 18 healthy subjects performed two acute experimental trials after the ingestion of p-synephrine (3 mg/kg) or placebo (cellulose). The main outcomes were: p-synephrine intake did not modify energy expenditure, fat and carbohydrate oxidation rate at rest, nor increase heart rate, systolic or diastolic blood pressure; however, it significantly increased fat oxidation rate at the same relative workload at intensities ranging from low to moderate while reducing carbohydrate utilization during exercise; and it did not modify energy expenditure or heart rate during exercise of increasing intensity.

A dose–response investigation of different doses of p-synephrine on maximal fat oxidation during exercise enrolled 17 healthy subjects in a double-blind and randomized design composed of four identical trials. Participants ingested a placebo or 1, 2, or 3 mg/kg of p-synephrine, rested for 60 minutes to allow substance absorption, then performed an exercise test of increasing intensity on a cycle ergometer while gas exchange was measured continuously. None of the doses of p-synephrine affected energy expenditure or heart rates during the test.

In contrast, a subsequent study specifically in women found different results: using a double-blind, randomized experiment, 18 healthy recreationally active women performed two identical exercise trials after ingesting 3 mg/kg of p-synephrine or placebo. Compared to placebo, p-synephrine increased resting tympanic temperature (36.1 ± 0.5 vs. 36.4 ± 0.4 °C, p = 0.033) with no effect on resting heart rate or blood pressure. During exercise, there was no significant effect of p-synephrine on fat oxidation rate, carbohydrate oxidation rate, energy expenditure rate, heart rate, or perceived exertion. The maximal rate of fat oxidation with placebo was 0.26 ± 0.10 g/min and was similar with p-synephrine (0.28 ± 0.08 g/min, p = 0.449).

Several investigations have found that the intake of 2–3 mg/kg of p-synephrine raises fat oxidation rate during exercise of low-to-moderate intensity; however, these investigations have been carried out only with samples of male participants or mixed men/women samples.

Evidence strength assessment: There is some preliminary, inconsistent evidence from small acute studies that p-synephrine at doses of 2–3 mg/kg may increase fat oxidation during low-to-moderate intensity exercise in men, but the finding was not replicated in women. No evidence exists for meaningful effects on sports performance outcomes in the longer term. All studies are acute, small, and in healthy recreationally active populations.

5.3 Anxiety, Sedation, and Neurological Effects

More recently, bitter orange extracts have been demonstrated to possess anxiolytic and sedative properties. This has been documented primarily in animal models. In mice, the anxiolytic and sedative effects of bitter orange extract were compared with chlordiazepoxide 10 mg/kg, valproic acid 400 mg/kg, or diazepam 1.2 mg/kg; mice were treated orally with 1 g/kg of the extract, and after 30 minutes each animal was injected with sodium pentobarbital 40 mg/kg.

Preparations from the peel, flowers, and leaves of Citrus aurantium L. are commonly used to decrease central nervous system disorders.

Evidence strength assessment: Evidence for anxiolytic and sedative effects of bitter orange extracts is limited to animal models. No adequately powered human clinical trials have investigated synephrine's effects on anxiety, mood, or neurological conditions.

5.4 Digestive and Gastrointestinal Applications

In traditional medicine, Citrus aurantium was used for digestive issues such as indigestion, bloating, and gas. However, no double-blind, placebo-controlled trials have been performed on Citrus aurantium for this purpose.

Evidence strength assessment: Traditional use for digestive applications is well-documented across multiple systems of medicine, but no controlled clinical evidence exists to support or refute these applications.

5.5 Other Investigated Areas

Citrus aurantium has been suggested for its antibacterial, anti-inflammatory, and antioxidant properties, as well as possible applications in treating anxiety and depression; however, scientific support for these uses is largely preliminary and requires further investigation. The leaf and flower have been studied for anticancer activity and as antispasmodics and sedatives. The peel has been studied as a digestive aid, demulcent, tonic, and vascular stimulant, as well as an anti-inflammatory, antibacterial, and antifungal agent, and for reducing cholesterol. These areas remain at the level of in vitro or animal studies with no substantive human clinical trial evidence.

6. Body Systems and Health Areas of Association

• Sympathetic / adrenergic nervous system: Citrus aurantium contains constituents — most frequently cited as synephrine and octopamine — which are structural analogs of adrenaline and noradrenaline respectively, and can act as adrenoceptor agonists.
• Cardiovascular system: Synephrine is a primary synthesis compound with pharmacological activities including vasoconstriction, elevation of blood pressure, and relaxation of bronchial muscle.
• Metabolic / adipose system: Bitter orange extract is used in weight management products due to its purported effects on metabolic processes, including an increase in basal metabolic rate and lipolysis, as well as mild appetite suppression.
• Liver metabolism: p-Synephrine, as an adrenergic agonist, is expected to affect liver metabolism. Epinephrine, norepinephrine, and other adrenergic agonists stimulate glycogenolysis and gluconeogenesis in the liver via α- and β-adrenoreceptors.
• Central nervous system: Preparations from the peel, flowers, and leaves of Citrus aurantium are commonly used to decrease central nervous system disorders.
• Respiratory system: In traditional Chinese medicine, bitter orange has been used as an expectorant.

7. Dosage Forms and Doses Reported in Clinical Studies

Bitter orange extracts are aqueous/ethanolic extracts of the dried immature fruits of C. aurantium that are harvested in May and June. The following dosage information derives solely from reported research and review data:

• p-Synephrine doses in clinical studies have ranged from 10 to 53 mg/day when consumed alone or in combination with caffeine (132–528 mg/day).
• In a double-blind, placebo-controlled study, 46 healthy human subjects were given bitter orange extract (49 mg p-synephrine) twice a day — a total of 98 mg/day of p-synephrine — for 60 days, while 23 subjects received placebo. No cardiovascular effects were observed, nor were there adverse effects with respect to blood chemistries or blood cell counts.
• One study examining resting metabolic rate used 50 mg p-synephrine (from Advantra Z®, 60% p-synephrine) in 40 subjects, observing a 6.9% increase in resting metabolic rate at 75 minutes post-ingestion.
• Exercise studies have used acute doses of 3 mg/kg body weight of p-synephrine, with an absorption period of approximately 60 minutes before exercise.
• A dose–response exercise study tested doses of 1, 2, and 3 mg/kg p-synephrine.
• One cardiovascular safety study had 12 subjects consume 8 ounces of orange juice (approximately 13 mg p-synephrine) in a crossover design, followed by repeat ingestion 8 hours later.
• A 14-day clinical trial using a commercial product (Xenadrine EFX®) with exercise involved 16 healthy overweight or obese subjects consuming two capsules twice daily, containing a total of 24 mg p-synephrine/day.

Over 30 clinical human studies with in excess of 700 subjects, along with animal and in vitro studies, have assessed the safety, efficacy, and mechanism of action of Citrus aurantium extract and its primary active constituent p-synephrine.

8. Safety Considerations and Interactions

8.1 Cardiovascular Safety: Clinical Trial Data

p-Synephrine alone or in combination with other herbal ingredients generally did not produce significant adverse events such as increases in heart rate or blood pressure, or alter electrocardiographic data, serum chemistry, blood cell counts, or urinalysis, in clinical trials reviewed up to 2012.

However, the more comprehensive 2022 systematic review and meta-analysis found a different picture when aggregating prolonged-use data: both systolic and diastolic blood pressure 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).

8.2 Adverse Event Case Reports

A systematic review of case reports collected through August 2021 found 30 case reports describing a total of 35 patients who suffered from medical complaints following use of synephrine-containing supplements. Patients most often presented with chest pain, palpitations, syncope, and dizziness. Commonly raised diagnoses were ischaemic heart disease, cardiac arrhythmias, and cerebrovascular disease. Five patients were left disabled or remained on medication at last follow-up. The review demonstrated an association between the use of pre-workout supplements containing synephrine and adverse events, mainly related to the cardiovascular system.

However, an important interpretive caveat applies. A review of 22 FDA adverse event reports from April 2004 through October 2009 associated with bitter-orange-containing products, as well as 10 clinical case reports linking bitter-orange-containing weight management products with cardiovascular incidents, found that in each case the authors implicated bitter orange extract and/or p-synephrine as the possible causative agent. However, in all adverse event reports and case reports, the products involved were polyherbal, polyalkaloidal, and poly-protoalkaloidal; consequently, it is not possible or plausible to ascribe the observed effects to a single ingredient.

8.3 EFSA and Regulatory Safety Assessment

C. aurantium has been used as a case study by the EFSA Scientific Cooperation (ESCO) Working Group on botanicals and botanical preparations. EFSA concluded that for the traditional food uses of bitter orange, there is no presumed safety concern. However, EFSA indicated that for the safety assessment of the use of bitter orange preparations with a p-synephrine content above 6%, additional data are required, including data on absorption, distribution, metabolism, excretion (ADME), genotoxicity, long-term toxicity, and developmental toxicity.

8.4 Interaction with Monoamine Oxidase Inhibitors (MAOIs)

Synephrine can interact with monoamine oxidase inhibitors, resulting in an increase of synephrine concentration in the blood and an increased risk of adverse effects. As a trace amine metabolized partly by monoamine oxidase, concurrent MAOI use would be expected to impair synephrine clearance. This represents a clinically relevant drug–supplement interaction that has been highlighted in multiple regulatory and pharmacological assessments.

8.5 Combination with Other Stimulants

More than one substance with potential effects on the cardiovascular system and/or sympathomimetic action has frequently been co-consumed with synephrine in real-world usage, including 1,3-dimethylamylamine, oxilofrine, deterenol, yohimbine, caffeine, and theophylline. The safety implications of such combinations have not been adequately studied in humans.

In clinical investigations, approximately 35% of human subjects concurrently consumed caffeine, a stimulant thermogenic agent. In these clinical investigations, no serious adverse effects were reported or observed when using the combination of p-synephrine with caffeine. Animal studies with exceedingly high doses of p-synephrine in combination with caffeine support and affirm the human studies. It should be noted that published studies involving caffeine and p-synephrine have been short-term in nature.

8.6 Sports Doping Status

Synephrine has been added to the Monitoring Program in Competitions of the World Anti-Doping Agency (WADA), but as of 2022 was not yet considered a prohibited substance by WADA. However, it is prohibited for use by several professional sporting agencies.

8.7 Product Labeling and Concentration Concerns

There is currently no legislation that limits the content of synephrine and other alkaloids in dietary supplements based on EU Directive 2002/46/EC, although each country is supposed to set a maximum level of synephrine. There have been reports in the Rapid Alert System for Food and Feed (RASFF) about synephrine, because in some countries a limit regarding its daily dose exists, and reported cases involved products that contained more than the established maximum.

8.8 Distinguishing p-Synephrine from m-Synephrine (Phenylephrine)

A frequently cited but important methodological concern is the conflation of p-synephrine with m-synephrine (phenylephrine). One early study cautioned that individuals with tachyarrhythmias, severe hypertension, narrow-angle glaucoma, and those taking monoamine oxidase inhibitors should avoid Seville orange juice; however, this warning was based on the erroneous assumption that the form of synephrine present in the orange juice was m-synephrine. Phenylephrine/m-synephrine has substantially greater α-adrenergic potency than naturally occurring p-synephrine, and safety data from one isomer should not be applied to the other.

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