IngredientsAdrenergic amines — also referred to as sympathomimetic amines, biogenic amines, or trace amines depending on context — are a chemically related group of naturally occurring compounds capable of activating or mimicking the actions of the sympathetic nervous system. Sympathomimetic agents are a group of chemical compounds that are able to activate the sympathetic nervous system either directly via adrenergic receptors or indirectly by increasing endogenous catecholamine levels or mimicking their intracellular signaling pathways. In the dietary supplement context, the term "adrenergic amines" most precisely denotes a cluster of five naturally occurring phenylethylamine-derived compounds found at exploitable concentrations in Citrus species: p-synephrine, p-octopamine, tyramine, N-methyltyramine, and hordenine (N,N-dimethyltyramine), with ephedrine alkaloids from Ephedra sinica representing a closely related but pharmacologically distinct sub-class. Certain plants contain adrenergic amines of the group consisting of synephrine, hordenine, octopamine, tyramine and N-methyltyramine; however, useful and exploitable levels of these adrenergic amines only occur in plant species of Citrus.
Compounds from this group comprise endogenous catecholamines (such as adrenaline and noradrenaline), synthetic amines (e.g., isoproterenol and dobutamine), trace amines (e.g., tyramine, tryptamine, histamine and octopamine), illicit drugs (e.g., ephedrine, cathinone, and cocaine), or even caffeine and synephrine. Adrenergic amines as dietary supplements or functional food ingredients are primarily represented by the plant-sourced trace amines from Citrus aurantium (bitter orange) and the ephedra alkaloids from Ephedra sinica.
Phenethylamine alkaloids originate from the amino acid l-tyrosine from small modifications in its molecule, and they are classified as protoalkaloids because they do not have the nitrogen atom as part of the ring. The shared phenylethylamine backbone is fundamental to their adrenergic activity: the phenylethylamine structure is basic to this activity, and hydroxylation of the ring amplifies pressor activity.
Synephrine exists in three different positional isomers; however, only p- and m-synephrine have been described in weight-loss products. This distinction is pharmacologically critical: m-synephrine is a more potent adrenergic stimulant than p-synephrine. M-synephrine, a more potent isomer of synephrine, does not naturally occur in C. aurantium, but is sometimes added to C. aurantium supplements. Consequently, products labelled as containing synephrine may have substantially different pharmacological profiles depending on which isomer is present.
Citrus species are rich sources for various bioactive compounds such as flavonoids, adrenergic amines, limonoids, and coumarins. The commercially dominant source is the immature (unripe) fruit and peel of Citrus aurantium L. (bitter orange, Seville orange). C. aurantium extract is widely known as bitter orange extract, a product that is derived from the immature (green) fruits of the Seville orange. It is also known as "Chih-shi" or "Zhi shi" in traditional Chinese medicine.
Measured concentrations vary substantially across plant parts and species. Synephrine concentrations in C. aurantium fruit extracts and fruit parts include: whole fruit extract 600 μg/g; exocarp 1100 μg/g; mesocarp 580 μg/g; and endocarp + juice 94 μg/g. Synephrine was present in levels from 3.65 to 60.66 mg/L in 48 Citrus juices and 0.018–1.02 mg per serving in 32 Citrus jams. In its natural state, p-synephrine is the main phytochemical in most of these fruits, and it is present in the range of 0.10–0.35% in fruits of Citrus aurantium and in the range of 3.00–3.08% in dry extracts of this fruit.
Synephrine has been detected in orange honey at concentrations of 79.2 to 432.2 ng/g and is proposed as a botanical marker to attest the authenticity of orange honey.
Tyramine and its derivatives, including N-methyltyramine and hordenine, are also found in plants beyond Citrus. Phenethylamines are found in many plant families throughout the plant kingdom; particularly rich in variously substituted phenethylamines are the families Cactaceae and Leguminosae. Most common among the natural phenethylamines are para-hydroxylated derivatives, tyramine, N-methyltyramine, and hordenine, and these compounds occur in most of the plant families. Ginkgo biloba extracts also contain these derivatives: the total content of the four tyramine derivatives in various Ginkgo biloba extracts ranged from 7.3 up to 6357 μg/g dry extract, with N-methyltyramine and hordenine as the most abundant ones.
Ephedra sinica (also known as Chinese ephedra or ma huang) is a species of Ephedra in the plant family Ephedraceae. Native to Mongolia, northern China, and Russia, it is a shrub found on arid highland slopes, dry river beds, steppes, fields, or mountain sides. Ephedrae herba (called Mahuang in China) is the dried herbaceous stem of Ephedra sinica Stapf, Ephedra intermedia Schrenk et C. A. Mey., and Ephedra equisetina Bge. While ephedrine is the most well-known constituent, it contains 6 other structurally similar alkaloids in lesser concentrations with similar effects.
Tyramine is unique among the adrenergic amines for its widespread occurrence as a food constituent independent of botanical supplement use. Tyramine occurs widely in plants and animals, and is metabolized by various enzymes, including monoamine oxidases. In foods, it is often produced by the decarboxylation of tyrosine during fermentation or decay. Foods that are fermented, cured, pickled, aged, or spoiled have high amounts of tyramine. Foods where typically high levels of biogenic amines occur are fermented food and beverage.
Ephedra sinica has a long history in traditional Chinese medicine (approximately 5,000 years), with uses in the treatment of allergies, nasal congestion, bronchial asthma, coughs, and flu. Ma huang is one of the earliest and best known drugs of Chinese traditional medicine. It is mentioned in the Shen Nong Ben Cao Jing, one of the premodern classics of Chinese medicine written around 100 AD. Ma huang was used to induce perspiration and treat the symptoms of bronchial asthma, colds, and influenza; it is still in traditional use today.
The traditional preparations were straightforward botanical decoctions. Known in the rest of the world as ephedra, ma huang had been used in traditional Chinese medicine as a stimulant and anti-asthmatic for more than 5,000 years. The dried stems and leaves of the Ephedra plant could be prepared as capsules, tablets, tinctures, and teas. Traditional use was not confined to China: various Ephedra plant species were also used in the Bronze Age Mediterranean (1050 BCE), by Greek physicians (50 CE), and in Russia (19th century), India, and Mexico. Native Americans and Mormon pioneers brewed other Ephedra species as a tea, called "Indian tea" and "Mormon tea," respectively.
Chemical investigations of ephedra in the early 20th century resulted in the isolation of the alkaloids ephedrine and pseudoephedrine, which were identified as the major pharmacologically active compounds in the aboveground portions of the plant. Following their isolation, the isolated chemical ephedrine became popular as a drug to enhance athletic performance, promote weight loss, and relieve colds and flu. When it was first discovered, its main use in pharmacy was as a bronchodilator to open up the airways of asthma sufferers.
C. aurantium extract is widely known as bitter orange extract, derived from the immature (green) fruits of the Seville orange. It is also known as "Chih-shi" or "Zhi shi" in traditional Chinese medicine. Its traditional applications differ markedly from its modern supplement use, which focuses on weight management. Traditional Chinese preparations used the dried unripe fruit peel primarily for digestive and respiratory conditions. 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. This contemporary weight-management application is a modern re-purposing that emerged after the regulatory actions against ephedra.
Synephrine became one of the most popular stimulants present in weight-loss products after the US Food and Drug Administration had interdicted the use of ephedrine-containing dietary supplements. p-Synephrine is mainly used in herbal products for weight-loss due to its purportedly lipolytic abilities. This use emerged as a safer alternative when ephedra and related products were banned from dietary products by the US Food and Drug Administration (FDA) in 2004.
Ephedrine is a sympathomimetic amine and exhibits multiple mechanisms of action that can consist either of a direct agonist effect on α- and β-adrenergic receptors or particularly of an indirect effect involving the release of catecholamines (noradrenaline and adrenaline). Ephedrine alkaloids act on the cardiovascular system directly by stimulating α1-, β1-, and β2-adrenergic receptors and indirectly by releasing norepinephrine from body stores. Their effects last much longer than those of epinephrine and consist primarily of an increase in heart rate and peripheral vascular resistance.
An important structural note: substitution at the α-carbon atom of ephedrine, amphetamine, and methamphetamine prevents oxidation by monoamine oxidase, making them longer-acting agents. Ephedrine is not considered a trace amine and is not found in the human nervous system.
The receptor pharmacology of p-synephrine is central to distinguishing it from ephedrine and m-synephrine (phenylephrine). The structural and stereochemical differences of p-synephrine and p-octopamine as related to ephedrine and m-synephrine result in markedly different adrenergic receptor binding characteristics. p-Synephrine and p-octopamine exhibit little binding to α-1, α-2, β-1 and β-2 adrenergic receptors, nor are they known to exhibit indirect actions leading to an increase in available levels of endogenous norepinephrine and epinephrine at commonly used doses.
Instead, evidence points to preferential activity at β-3 adrenergic receptors: p-synephrine has a poor binding affinity to α1, α2, β1 and β2 adrenergic receptors. However, p-synephrine activates β3 adrenergic receptors that may be responsible for the increased fat utilization during exercise through modulation of lipolysis via the epinephrine- and norepinephrine-induced activation of adenylate cyclase. If p-synephrine binds to and activates β-3 adrenoreceptors, an increase in thermogenesis and lipolysis should be expected.
The desired effect of synephrine is caused by stimulation of beta-3 adrenoreceptors and thereby increasing lipolysis and metabolic rate. However, synephrine intake might also lead to cardiovascular effects by the stimulation of additional adrenergic receptors (beta-1 and beta-2).
In addition to the effects triggered by stimulation of the sympathetic system, the discovery of trace amine-associated receptors (TAARs) in humans brought new insights about their sympathomimetic pharmacology and toxicology. The most prominent biogenic amines which interact with TAARs include p-octopamine, tyramine, tryptamine and β-phenylethylamine, although N-methyltyramine, p-synephrine and 3-iodothyronamine have also been included as trace amines. All three amines (tyramine, octopamine, and synephrine) have been shown to activate human TAAR-1 expressed in cloned cells and increase cAMP levels, with tyramine being the most potent.
The TAARs constitute another mechanism whereby p-synephrine and p-octopamine as well as N-methyltyramine and tyramine may exert various physiological and pharmacological effects either by acting as neurotransmitter precursors or neuromodulators, and serve as biomarkers. Vascular studies using isolated tissues have revealed tissue-specific pharmacology: results suggest complex responses of the coronary artery to the trace amines, with activity at α1-adrenoceptors and potentially TAARs other than TAAR-1. In contrast, the actions of the amines on the mesenteric artery appeared to involve indirect sympathomimetic actions and direct actions on α1-adrenoceptors.
In comparative studies of lipolytic activity, p-octopamine was the most selective for beta-3 adrenergic receptors, stimulating lipolysis in rat, hamster and dog adipocytes. 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. In human adipocytes specifically, 10 μg/ml of both synephrine (p-synephrine) and p-octopamine exhibited approximately 10% of the lipolytic activity of 1 μM/ml of isoprenaline. This finding highlights important species differences that limit the extrapolation of animal data to human outcomes.
In some vascular tissues, tyramine has been shown to act as an indirectly acting sympathomimetic agent, promoting the release of endogenous noradrenaline. For over 50 years, trace amines have been assumed to be indirectly acting sympathomimetic amines, their responses being due to the release of noradrenaline from sympathetic neurones. Under physiological conditions, alimentary tyramine is degraded by MAO-A to prevent systemic uptake. Tyramine may act as an indirect sympathomimetic agent. Tyramine is a substrate for the noradrenaline transporter molecule situated in the plasma membrane of sympathetic nerves and adrenal medulla, as well as the vesicular transporter situated in the membrane of storage vesicles.
N-methyltyramine is rapidly absorbed and undergoes N-demethylation to tyramine followed by rapid oxidative deamination. Hordenine showed no changes in heart rate, respiratory rate, body temperature or behavior when given orally at a dose of 2 mg/kg to horses. Therefore, no effect would be projected in a human that consumed several mg of N-methyltyramine and hordenine from a typical dose of an average beer or a standardized bitter orange extract.
Evidence Level: Mixed to Weak (Human Data)
The body of human clinical research on the adrenergic amines from Citrus aurantium for weight loss is notable primarily for its limited scale. The results of over 20 studies involving a total of approximately 360 subjects that consumed p-synephrine alone or in combination with other ingredients have been reviewed. Over 50% of the subjects involved in these studies were overweight/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.
A 2012 narrative review of human clinical data concluded that in general, bitter orange extract alone (p-synephrine) or in combination with other herbal ingredients did not produce significant adverse events as an increase in heart rate or blood pressure, or alter electrocardiographic data, serum chemistry, blood cell counts or urinalysis. p-Synephrine alone as well as in combination products were shown to increase resting metabolic rate and energy expenditure, and modest increases in weight loss were observed with bitter orange extract/p-synephrine-containing products when given for six to 12 weeks. Longer term studies are needed to further assess the efficacy of these products and affirm their safety under these conditions.
However, a subsequent systematic review and meta-analysis (including 18 placebo-controlled human clinical trials) reached more cautionary conclusions: 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.
An early double-blind, placebo-controlled, randomized study by Colker et al. found that subjects receiving a combination of Citrus aurantium, caffeine and St. John's Wort lost significant amounts of total body weight while on a strict diet and exercise, while those in the placebo and control groups who also were on the same restricted diet did not. However, intergroup analysis showed no statistical significance among the weight changes in the three groups. In contrast, the loss of fat mass in the test group was significantly greater compared to the placebo and control groups.
Sympathomimetic agents have a poor history of long-term success in the treatment of obesity. From earlier experiences with amphetamine and its analogs, to more recent drugs with direct effects on adrenergic receptors or indirect effects from release of catecholamines or inhibition of reuptake, cardiovascular toxicity (strokes and cardiac arrhythmias) has been the major concern. These concerns also extended to food supplements containing ephedra alkaloids and may require consideration for current supplements containing the sympathomimetic drug, synephrine.
Evidence Level: Moderate for Fat Oxidation in Males; Inconsistent by Sex
A series of controlled human studies, primarily from Spanish research groups, has examined p-synephrine's effects on substrate oxidation during exercise. A 2016 study published in the British Journal of Clinical Pharmacology used a double-blind design: the ingestion of 3 mg/kg of p-synephrine did not change energy consumption or fat oxidation rate at rest. However, acute consumption of p-synephrine was effective to move the fat oxidation–exercise intensity curve upwards during the incremental exercise and increased maximal fat oxidation rate during exercise. The metabolic effects found after the ingestion of p-synephrine might be valuable for those individuals seeking increased fat oxidation during exercise.
A dose-response study using 17 healthy subjects in a double-blind, randomised, four-trial design tested 1, 2, or 3 mg/kg of p-synephrine against placebo: none of the doses of p-synephrine affected energy expenditure or heart rates during the test. A narrative review of the exercise literature summarised the pattern of evidence: 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. Previous investigations have demonstrated that the acute intake of p-synephrine does not modify running sprint performance, jumping capacity, or aerobic capacity.
However, sex differences appear to modulate response. A 2022 double-blind, randomized study of 18 healthy recreationally active women (3 mg/kg p-synephrine) found that during exercise, there was no significant effect of p-synephrine on fat oxidation rate, carbohydrate oxidation rate, energy expenditure rate, heart rate, or participant's perceived exertion. The investigators noted that several recent investigations found that the intake of 2–3 mg/kg of p-synephrine raises fat oxidation rate during exercise of low-to-moderate intensity, but these investigations had been carried out only with samples of male participants or mixed men/women samples.
Evidence Level: Preliminary (Small Human Studies)
The thermic effect of orally administered p-synephrine (26 mg) was demonstrated in a five-hour human clinical study involving 30 subjects. Additionally, the oral administration of 50 mg p-synephrine (30% p-synephrine as Advantra Z) increased resting metabolic rate with no effect on heart rate or blood pressure in humans in a double-blinded, randomized placebo-controlled study. These findings remain preliminary given the small sample sizes and short durations characteristic of available studies.
Evidence Level: Established but Regulatory Status Limits Supplement Use
Ephedrine had been used to treat or prevent hypotension, and has been used for asthma, obesity and narcolepsy. In the clinic, Ephedrae herba is commonly used for treating colds, bronchial asthma, nasal congestion, and other diseases. Ephedra is a genus of plants, one species of which is known as Ma huang or Ephedra sinica, the prime source of ephedra alkaloids, including ephedrine and pseudoephedrine, which have been used for centuries to treat bronchoconstriction, because of their activity at β2-adrenergic receptors. This pharmacological mechanism is well-established in the clinical literature, though the use of ephedrine-containing dietary supplements for such purposes has been heavily curtailed by regulatory bans in many jurisdictions.
Adrenergic amines interact with multiple physiological systems by virtue of their adrenergic receptor activity. The principal body systems implicated are:
The composition can be administered in the form of the plant material in a tablet, capsule or other pharmacologically appropriate carrier, in the form of a tea, or in the form without plant material in a tablet, capsule or other pharmacological carrier which contains at least one of the group of five adrenergic amines extracted from the plant material.
Commercially, the amount of p-synephrine can be artificially increased by concentrating the extract of natural products, and p-synephrine may be in a concentration of up to 19% in some commercially available dietary supplements.
The following dosages are reported specifically in the cited human clinical studies:
Ephedrine and related alkaloids have been associated with adverse cardiovascular events, including acute MI, severe hypertension, myocarditis, and lethal cardiac arrhythmias. Dietary supplements that contain ephedra alkaloids were widely promoted and used in the U.S. for weight loss and increased energy. Their use was associated with a number of adverse events, including MI, stroke, arrhythmias, and death, and in December 2003 the FDA announced a ban on the sale of ephedra products in the U.S.
Extracts of Ephedra shrubs contain highly active α- and β-adrenergic agonists that have profound effects on the heart and vasculature. Evidence for their effectiveness is limited. Adverse cardiovascular and cerebrovascular effects, including stroke, myocardial infarction, and sudden death, temporally related to their use are well described. Due to concerns about alkaloid toxicity, ephedrine has been banned from the market in the European Union, United States, and many other countries.
Concerns regarding synephrine safety due to its structural and pharmacological similarities with other sympathomimetic amines have emerged with new data. The 2022 meta-analysis (18 placebo-controlled studies) documented that both systolic and diastolic blood pressure increased significantly after prolonged use (6.37 mmHg, 95% CI: 1.02–11.72 and 4.33 mmHg, 95% CI: 0.48–8.18, respectively).
One case report documented that in an otherwise healthy young man with no defined risk factors, an ischemic stroke was associated with recent use of Stacker 2 Ephedra Free, a supplement containing the vasoactive sympathomimetic amine synephrine and caffeine. A systematic review of case reports found that there is an association between the use of pre-workout supplements containing synephrine and adverse events, mainly related to the cardiovascular system. However, a role of possible confounding factors such as caffeine cannot be excluded. Thus, the use of pre-workout supplements containing synephrine may lead to serious adverse health events, and caution is needed.
Some investigators argue that p-synephrine's receptor profile renders it less dangerous than ephedrine. No cardiovascular or other adverse effects have been observed in over 30 controlled human studies involving typical oral doses of p-synephrine in the range of 25–100 mg. However, the 2022 meta-analysis directly contradicts this view with respect to blood pressure, underscoring that the safety debate remains unresolved.
When weight-loss products employ high doses of synephrine or synephrine in combination with ingredients such as caffeine, salicin, and ephedrine, the whole mixture can be associated with cardiovascular injury. Although p-synephrine is generally considered to be safer than ephedra, controversy surrounds its toxic effects, especially in combination with caffeine, which is known to potentiate the cardiovascular effect of p-synephrine. It is thought that the combination of synephrine and caffeine may lead to synergistic effects in fat burning, but might also increase the risk of cardiovascular adverse effects.
The interaction between tyramine and monoamine oxidase inhibitors (MAOIs) represents one of the most clinically important and well-documented drug-food interactions in pharmacology. In humans, if monoamine metabolism is compromised by the use of monoamine oxidase inhibitors (MAOIs) and foods high in tyramine are ingested, a hypertensive crisis can result as tyramine can cause the release of stored monoamines, such as dopamine, norepinephrine, epinephrine. This occurs because under physiological conditions, alimentary tyramine is degraded by MAO-A to prevent systemic uptake. When MAO-A is inhibited, this protective mechanism fails. When foods high in tyramine are ingested by a subject who is consuming MAO-A inhibitors, there is a sudden surge in the tyramine level and subsequently the level of noradrenaline also rises. This sudden increase in the level of noradrenaline drastically increases the blood pressure and can lead to fatal consequences.
Relevant foods high in tyramine include: strong or aged cheeses (cheddar, Swiss, Parmesan, Stilton, Gorgonzola or blue cheeses, Camembert, feta, Muenster); meats that are cured, smoked, or processed (such as salami, pepperoni, dry sausages, hot dogs, bologna, bacon, corned beef, pickled or smoked fish, caviar, aged chicken livers); and pickled or fermented foods (sauerkraut, kimchi, tofu, pickles, miso soup, bean curd, tempeh, sourdough breads).
Nine commercially available ephedra supplements exhibited considerable variability in alkaloid content (ephedrine range: 1.08–13.54 mg). Only three products listed ephedrine content on the label while one exhibited lot-to-lot variations in ephedrine of 137%. Similar issues exist for synephrine products: although the presence of m-synephrine in nature is controversial, this positional isomer is present in weight-loss products, meaning that either m-synephrine is really available in nature, or the so-called "natural products" have at least one synthetic component.
Health conditions that Adrenergic amines may help support.
Body systems that Adrenergic amines may help support.
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