Higenamine (Norcoclaurine)
1. Identity
Chemical Names and Classification
Higenamine (1-(4-Hydroxybenzyl)-1,2,3,4-tetrahydroisochinolin-6,7-diol), also called dl-demethylcoclaurine or norcoclaurine, is a plant-based benzylisoquinoline alkaloid, which was originally isolated from the root of Aconitum (a commonly used traditional Chinese herbal medicine) as an active cardiotonic compound by Kosuge in 1976. It belongs to the structural class of protoberberines. The IUPAC name for the compound is 1-[(4-hydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol, and its molecular formula and weight are C16H17NO3 and 271.31 g/mol, respectively.
The compound carries CAS registry number 5843-65-2. It is a structural analogue of catecholamines and possesses characteristics similar to those of adrenergic receptor ligands.
Botanical Sources
Higenamine [(±)-higenamine, norcoclaurine, 1-(4-hydroxybenzyl)-1,2,3,4-tetrahydro-6,7-isoquinolinediol] is an alkaloid found within numerous plant species, including Annona squamosa, Aconitum carmichaelii, and Plumula nelumbinis, some of which are commonly used within Asian and Chinese herbal medicines.
Based on published literature, Nelumbo nucifera, Tinospora crispa, Nandina domestica, Gnetum parvifolium, Asarum siebodii, Asarum heterotropoides, Aconitum carmichaelii, and Aristolochia brasiliensis are confirmed higenamine-containing plants. The compound is specifically found in Nandina domestica (fruit), Aconitum carmichaelii (root), Asarum heterotropioides, Galium divaricatum (stem and vine), Annona squamosa, and Nelumbo nucifera (lotus seeds).
Its inclusion within nutritional supplements can be via its natural presence within botanical ingredients or as a synthetic additive, often added in milligram amounts. Today, higenamine can be manufactured (synthesized) as well as extracted from such plants.
Common Forms and Preparations
As a dietary supplement ingredient, it has been marketed in products for weight loss, energy enhancement, and athletic performance. Higenamine is present in some nutritional supplements; products which are typically marketed for their stimulant/weight management properties. Higenamine may appear on product label declarations either as higenamine, its chemical name, or its inclusion may be inferred by reference to a botanical ingredient. In some cases where a botanical source is listed, the presence of higenamine is not always from natural sources, but may be chemically synthesised.
The synthetic ingredient higenamine is not a legal dietary supplement, although it may appear naturally in a variety of plants including Nandina domestica, which is commonly used in throat lozenges in Japan.
2. Traditional and Historical Use
Traditional Chinese Medicine (TCM)
Higenamine is an active compound extracted from the roots of Fuzi (Aconitum carmichaelii), which has been widely used in ancient Chinese medical texts for diseases characterized by severe physical decline or those on the verge of death. "Fu Zi" refers to the processed root of Aconitum carmichaelii Debeaux, also known as Chinese Aconite. "Fu Zi" was first recorded in Shen Nong Ben Cao Jing, and was categorized in the "lowest grade" due to its severe toxicity when misused, overdosed, improperly processed, or combined wrongly with other herbs.
Fuzi is the processed product of the daughter root of Aconitum carmichaeli Debx, recorded in Shennong's Classic of Materia Medica as hot-natured and pungent in flavor. Fuzi has been used as a traditional Chinese medicine in China for centuries and offers therapeutic potential for heart failure, rheumatoid arthritis, gastroenteritis, depression, and other diseases.
In China and Japan, the folk medicine Aconitum japonicum Thunb., a source of higenamine, has been widely used for centuries to treat collapse, syncope, rheumatic fever, painful joints, gastroenteritis, diarrhea, edema, bronchial asthma, various tumors, and some endocrinal disorders like menoxenia.
"Fu Zi" is broadly used in all kinds of TCM preparations and appears in 13.20% among 500 well-known and historically successful prescriptions. There are two famous TCM decoctions named "Si Ni Tang" and "Fu Shen Tang," in which the composition of "Fu Zi" exceeds 50% and 60%, respectively. For centuries these preparations were used to treat heart failure and collapse, myocardial infarction, and shock.
Throughout its long history of use, various processing methods including water scrubbing, soaking in vinegar, and boiling with Radix Glycyrrhizae and black beans have been employed to reduce the toxicity of Fuzi and to enhance its efficacy.
Traditional Use in Other Cultures and Plants
Traditional formulations with higenamine have been used for thousands of years within Chinese medicine and come from a variety of sources including fruit and orchids. Members of the genus Aconitum have been used for millennia, both as poisons and medicines, in Eastern culture.
Higenamine, an active ingredient of Aconiti Lateralis Radix Praeparata, has been traditionally used as a heart stimulant and anti-inflammatory agent in oriental countries. Based on data from Eastern folk medicine, higenamine-containing plants can provide numerous health benefits. Professional athletes may ingest these plants without knowing that they contain higenamine; these herbs are used in treatments for different conditions and various foods and food supplements in addition to folk medicine.
3. Key Constituents and Active Compounds
Chemical Structure and Biosynthetic Role
Higenamine, also known as norcoclaurine or dl-demethylcoclaurine, is a plant-based alkaloid which belongs to the structural class of protoberberines. It was initially isolated as the active cardiotonic component from Aconitum by Kosuge in 1976. In the context of the higenamine-containing parent plants, higenamine is only one of several biologically active alkaloids present. For example, Fuzi is composed of various alkaloids, such as diester diterpenoid alkaloids, aconitine, hypoaconitine, and higenamine (HG). It also contains lipids, such as fatty acids, phosphatidate calcium, and steroids.
Pharmacological Properties
Studies over the last four decades on higenamine have revealed its various pharmacological properties such as positive inotropic and chronotropic effect, activating slow channel effect, vascular and tracheal relaxation effect, anti-thrombotic, anti-apoptotic and anti-oxidative effect, anti-inflammatory and immunomodulatory effect.
4. Mechanisms of Action
Adrenergic Receptor Activity
Higenamine acts as an agonist of β1- and β2-adrenergic receptors (β1-/β2-AR). Because higenamine is structurally similar to catecholamines, it can activate both β1-AR and β2-AR; however, the exact mechanism of action of higenamine remains unknown.
Higenamine may act as a β-AR agonist and an α-AR inhibitor. Using a high-throughput screening assay, researchers identified higenamine to be a potent β-adrenergic receptor agonist. Further experiments using specific inhibitors showed that higenamine activated both β1-adrenergic receptor and β2-adrenergic receptor. Inhibition of its action by pertussis toxin (a Gi inhibitor) indicated that it is a β2-adrenergic receptor Gs/Gi dual agonist. Contractility experiments demonstrated a positive inotropic effect of higenamine.
Studies conducted in isolated in vitro systems, whole-animal preparations, and a small number of clinical studies suggest that higenamine acts in part as a β2-adrenoceptor agonist. In silico predictive tools indicated that higenamine and possibly a metabolite have a high probability of interacting with the β2-receptor as an agonist.
Research suggests that higenamine may also interact with other receptor systems such as α-receptors and dopamine receptors, although these effects are less well understood. The exact mechanism of action, particularly in relation to its activity at β3-receptors, is still under investigation, as β3-adrenergic activation can influence lipolysis and thermogenesis, potentially enhancing fat burning and metabolic rate.
Second Messenger Signaling
The adrenoceptors share the same messenger, cyclic adenosine monophosphate (cAMP). Higenamine partly exerts its actions by the activation of an enzyme, adenylate cyclase, responsible for boosting the cellular concentrations of the adrenergic second messenger, cAMP.
Downstream Signaling Pathways
In addition, higenamine can activate beta-adrenergic receptor (β-AR) signal transduction, which is involved in the PI3K/AKT signalling pathway. The heart protection and therapeutic effects of higenamine on heart disease are related to regulating LKB1/AMPKα/Sirt1, mediating the β2-AR/PI3K/AKT cascade, induction of heme oxygenase-1, suppressing TGF-β1/Smad signaling, and targeting ASK1/MAPK (ERK, P38)/NF-kB signaling pathway.
Ion Channel Effects
Higenamine is a benzylisoquinoline alkaloid with various pharmacological effects, including vasodilation, anti-platelet activity, and calcium channel-blocking activity. Higenamine can affect the movement of ions inside and outside the cell.
Overview of Verified Pharmacological Activities
Higenamine possesses anti-oxidant, anti-apoptotic, anti-inflammatory, electrophysiology regulatory, anti-fibrotic, and lipid-lowering activities. It can modulate multiple targets, including anti-inflammation- and anti-apoptosis-related targets and some transcription factors, which directly or indirectly influence the disease course.
5. Scientific Evidence by Area of Use
5.1 Cardiovascular System: Heart Failure, Bradyarrhythmia, and Cardiac Function
Higenamine, a natural product with multiple targets in heart diseases, is originally derived from Aconitum, which has been traditionally used in China for the treatment of heart disease, including heart failure, arrhythmia, bradycardia, cardiac ischemia/reperfusion injury, cardiac fibrosis, etc.
In humans, higenamine has been studied as an investigational drug in China for use as a pharmacological agent for cardiac stress tests as well as for treatment of a number of cardiac conditions including bradyarrhythmias. The human trials were relatively small (ranging from 10 to 120 subjects) and higenamine was administered intravenously, most commonly using gradual infusions of 2.5 or 5 mg. Higenamine consistently increased heart rate but had variable effects on blood pressure. One small study described higenamine's effect on cardiac output: higenamine led to an increased ejection fraction in 15 patients with heart disease.
Several clinical studies have reported that higenamine could continuously increase the heart rate levels of healthy volunteers as well as patients with heart disease, but there are variable effects on systolic blood pressure and diastolic blood pressure.
Studies have shown that the positive inotropic effect of higenamine and the effect of increasing heart rate (HR) are shorter than that of dobutamine hydrochloride. Higenamine can play the role of positive chronotropic effect and positive inotropic effect by regulating β1-AR. By regulating the β2-AR, higenamine has the effect of reducing the tension of smooth muscles, thus reflecting the effect of cardiac stimulation. Furthermore, higenamine enhances myocardial contractile response and reduces myocardial cell apoptosis by activating β2-AR.
Higenamine has effects on improving energy metabolism of cardiomyocytes, anti-cardiac fibroblast activation, anti-oxidative stress, and anti-apoptosis. Accumulating evidence from various studies has shown that higenamine exerts a wide range of cardiovascular pharmacological effects in vivo and in vitro, including alleviating heart failure, reducing cardiac ischemia/reperfusion injury, attenuating pathological cardiac fibrosis and dysfunction.
Evidence strength: The human/clinical evidence for cardiovascular effects is limited and preliminary. Trials were small (10–120 subjects), conducted primarily in China, and used exclusively intravenous administration. The safety of orally administered higenamine in humans is unknown. Most mechanistic data is derived from animal and in vitro studies.
5.2 Cardiac Stress Testing
Higenamine has been tested as a candidate pharmacologic stress agent in the detection of coronary artery diseases (CADs), and researchers have accomplished phase III clinical studies successfully in China. The scientific literature about higenamine's health effects is scant, limited to studies from China in which the stimulant was used to simulate cardiac stress tests for when a patient cannot run on a treadmill. Those studies said small amounts injected intravenously made the heart beat faster, pumping more blood in a way that replicated exercise.
Higenamine has been tested as a candidate pharmacologic stress agent in the detection of coronary artery diseases (CADs) in human clinical studies in China. Intravenous administration of 22.5 μg/kg higenamine was reported to be well-tolerated in healthy volunteers.
Evidence strength: Phase III clinical trial data exists in China for this investigational use. However, this evidence base is not yet translated into regulatory approval in major Western markets, and studies have been conducted primarily with intravenous dosing rather than oral supplementation.
5.3 Ischemia–Reperfusion Injury
Studies have shown that higenamine improves cardiac function, reduces myocardial injury, and exerts a protective effect in ischemia–reperfusion injury. Higenamine has anti-inflammatory, anti-oxidative, and anti-apoptotic capacities and has been successfully used in myocardial and intestinal ischemia reperfusion models. In a rat model of cerebral ischemia-reperfusion (I/R), higenamine improved functional state of nerves, significantly inhibited the I/R-induced increase in the serum level of tumor necrosis factor α (TNF-alpha) and interleukins such as IL-1, IL-6 and IL-18, and CD14+ cells, while decreasing axonal nerve degeneration.
In an in vitro intestinal epithelial cell model, higenamine increases cell viability through induced heme oxygenase-1 (HO-1) production. In an in vivo murine intestinal I/R injury model, the increased HO-1 protein level and activity, decreased intestinal injury score, myeloperoxidase (MPO) activity, and inflammatory cytokine expression induced by higenamine were all abolished with additional treatment of an HO-1 inhibitor, indicating HO-1 mediates protective effects.
Evidence strength: Preliminary; this evidence is largely restricted to animal models (rat, mouse) and cell culture systems. No human clinical trials on ischemia-reperfusion injury have been reported in the published literature.
5.4 Bronchodilation and Respiratory Effects
Higenamine acts primarily as a β2-adrenergic agonist, like conventional bronchodilators such as salbutamol and terbutaline, which activate the β2-receptors on the smooth muscle cells of the bronchi. By binding to these receptors, higenamine promotes the relaxation of bronchial muscles, leading to expanded airways and improved airflow, which is crucial for alleviating respiratory symptoms associated with asthma and COPD. This mechanism of action suggests that higenamine could be beneficial in relieving bronchospasm and improving overall pulmonary function in patients with these conditions.
In a rodent model, it was found that higenamine produced cardiotonic, vascular relaxation, and bronchodilator effects.
Evidence strength: Mechanistic evidence from animal and in vitro studies supports a bronchodilatory role via β2-adrenergic activity. No independent human clinical trials of higenamine as a bronchodilator have been published in peer-reviewed literature. The traditional use of Aconitum-derived formulations for asthma provides historical context, but clinical evidence for higenamine specifically is absent.
5.5 Weight Loss and Lipolysis
As a non-selective beta-agonist, higenamine could also have agonistic activity on beta3-receptors mainly expressed in white adipose tissue, which could result in fat loss by stimulating fatty acid mobilization and, directly or indirectly, fat oxidation. However, a limited number of human studies have examined lipolytic and thermogenic effects of higenamine.
The results of the study on circulating free fatty acids and energy expenditure in healthy, young men and women suggest that dietary supplementation with higenamine can promote lipolysis and increase energy expenditure, with minimal contribution to increases in hemodynamic variables.
Evidence strength: Very weak. Only a very small number of human studies have examined these endpoints, and the overall evidence base is inadequate to establish efficacy for weight loss or significant lipolysis from oral supplementation.
5.6 Exercise Performance
A randomized double-blinded placebo-controlled trial aimed to determine the ergogenic effects and safety profile of a one-component higenamine supplement in female recreational athletes. Twelve recreational female basketball players (age 29–41 years) were randomized either to the higenamine group or to the placebo group for 3 weeks. Variables assessed before and after supplementation included anthropometric parameters, resting metabolic rate, exercise testing variables, serum free fatty acids, blood pressure, enzyme activity, urea, lipid profile, and complete blood count. There were no differences between groups in anthropometric parameters, including basal metabolic rate, resting metabolic rate, body fat, or free fatty acids.
A key limitation of this study was its small sample of recreational athletes that potentially decreased the chance of finding significant differences in measured clinical outcomes.
Evidence strength: Very weak. The only identified randomized controlled trial in athletes found no statistically significant ergogenic benefit for higenamine supplementation. The trial was small (n=12) and of short duration. No additional robust human trials on athletic performance have been identified.
5.7 Anti-inflammatory and Antioxidant Effects
Emerging research has highlighted the anti-inflammatory and antioxidant properties of higenamine, suggesting that it may play a role in the management of various chronic diseases where inflammation and oxidative stress are major contributing factors. Chronic inflammation is a key driver of many conditions, including cardiovascular disease, diabetes, neurodegenerative disorders, and even some cancers.
The antioxidant effects of higenamine are related to free radical biology and medicine, and it can reduce the release of cytochrome C to reduce apoptotic cell death in rats with myocardial ischemia–reperfusion. In aqueous media, higenamine can exert its antioxidant effects through electron transfer and proton transfer, while in a lower pH environment, the ionization of H+ inhibits and weakens electron transfer.
Evidence strength: Preliminary. Evidence is derived from animal models and in vitro studies. No human clinical trials specifically examining anti-inflammatory or antioxidant endpoints for higenamine have been published.
5.8 Erectile Dysfunction
In a rodent model, via a beta-adrenoceptor mechanism, higenamine induced relaxation in rat corpus cavernosum, leading to improved vasodilation and erectile function.
Evidence strength: Preclinical (animal model) only. No human clinical trials have been identified.
6. Body Systems and Health Areas
Based on published pharmacological literature, higenamine has been associated with effects on the following body systems:
- Cardiovascular system: As a non-selective β-agonist, higenamine activates both β1- and β2-adrenergic receptors, leading to cardiovascular benefits such as increased heart rate and myocardial contractility, as well as bronchodilation.
- Respiratory system: Higenamine acts primarily as a β2-adrenergic agonist, like conventional bronchodilators, which activate the β2-receptors on the smooth muscle cells of the bronchi. By binding to these receptors, higenamine promotes the relaxation of bronchial muscles, leading to expanded airways and improved airflow.
- Metabolic system: Recent studies have shown that higenamine acts as a vasodilator and smooth muscle relaxant and helps in fat and blood glucose utilisation.
- Central and peripheral nervous system: Higenamine possesses neuroregulatory activity.
- Gastrointestinal system: Traditional preparations of Aconitum-based medicines were historically used for gastroenteritis and diarrhea, and higenamine has demonstrated anti-inflammatory and anti-apoptotic capacities in intestinal ischemia-reperfusion models.
- Reproductive system: Preclinical data indicate that via a beta-adrenoceptor mechanism, higenamine induced relaxation in rat corpus cavernosum, leading to improved vasodilation and erectile function.
7. Pharmacokinetics
Oral Bioavailability
The oral utilisation rate of higenamine is as low as 3–22%, which results in poor efficacy. While the pharmacokinetics of higenamine after intravenous administration has been intensively studied in animals and humans, the data are scarce regarding the oral route of administration in humans. The only data in the literature are those obtained in the rabbit and rat model showing very poor bioavailability of higenamine. Moreover, there are no studies providing data that would allow comparison of intravenous and oral doses of higenamine.
Intravenous Pharmacokinetics in Humans
The average concentration-time curve of higenamine in the plasma and the heart rate-time curve from healthy Chinese subjects after intravenous administration of 22.5 μg/kg (n=10) higenamine hydrochloride has been characterized in a Phase I pharmacokinetic study. The half-life of higenamine was 0.133 h (range, 0.107–0.166 h), while the area under the concentration-time curve (AUC), extrapolated to infinity, was 5.39 ng·h·mL−1. The volume of distribution was 48 L (range, 30.8–80.6 L). The total clearance was 249 L/h (range, 199–336 L/h). Within 8 hours, 9.3% (range, 4.6%–12.4%) of higenamine was recovered in the urine.
The pharmacokinetics of higenamine was successfully described using a two-compartment model with nonlinear clearance. In the pharmacodynamic model, heart rates were related to plasma drug concentrations using a simple direct effect model with baseline. The E0, Emax, and EC50 were 68 bpm, 73 bpm, and 8.1 μg/L, respectively.
Pharmacokinetic studies conducted in animals and humans showed that higenamine conformed to a two-compartment pharmacokinetic model.
8. Dosage Forms and Reported Dosages
Dosages Used in Human Clinical Studies
- In human studies reporting increased heart rate, variable effects on blood pressure, dyspnea, dizziness, and other adverse effects, higenamine was administered intravenously, mostly using gradual infusions in doses of 2.5 or 5 mg higenamine.
- A Phase I pharmacokinetic study in healthy Chinese subjects used intravenous administration of 22.5 μg/kg higenamine hydrochloride (n=10).
- In one 8-week oral supplementation study, participants continuously took higenamine capsules (50 mg per capsule) for 8 weeks, with no significant effect observed on men's resting breathing rate, heart rate, blood pressure, urine test indicators, complete blood count, metabolic indicators, liver enzyme activity, and blood lipids.
Dosages Found in Commercial Supplements
Label amounts in commercial products typically range 10–75 mg in a single serving. In a Clinical Toxicology study, researchers studied 24 products labeled as containing higenamine or the synonyms "norcoclaurine" or "demethylcoclaurine" and found unpredictable and potentially harmful quantities of the stimulant ranging from trace levels to 62 mg per serving. Of the 24 products tested, only five listed a specific quantity of higenamine on the label, and none of those five quantities were accurate. Based on the labeled directions for use, consumers could be exposed to up to 110 mg of higenamine per day.
Testing of products has shown that the actual amounts present often do not match the amounts declared on labels, with amounts ranging from less than 0.01% to 200% of declared quantities.
9. Safety Considerations and Regulatory Status
Established Adverse Effects
In drug trials conducted in China, subjects who received higenamine experienced symptoms such as dyspnea, palpitations, dizziness, headaches, and tightness in the chest, as well as increased heart rate and blood pressure. Identified as having mixed adrenergic receptor activity, clinical data relating to safety and efficacy of higenamine are extremely limited and the health risks of consumption are not currently understood.
Cardiotoxicity Concerns
The U.S. Food and Drug Administration (FDA) has determined higenamine to be a "new dietary ingredient (NDI) for which an NDI notification is required and has not yet been submitted." Therefore, any product containing higenamine is considered "adulterated." The FDA also points to higenamine's "potential for serious cardiotoxic effects."
The FDA has received reports of adverse effects from supplements containing higenamine since 2014, though the health risks are still poorly understood.
Label Accuracy and Consumer Risk
An international team of public health researchers published a peer-reviewed study documenting inaccurately labeled and potentially harmful levels of the stimulant in weight-loss and sports/energy supplements available in the United States. Some of these products contain extremely high doses of a stimulant with unknown safety and potential cardiovascular risks when consumed. What can be learned from published study findings is that there is often no way for a consumer to know how much higenamine is actually in the product they are taking.
WADA Prohibition and Doping Risk
The World Anti-Doping Agency (WADA) prohibited list has contained higenamine since 2017 as banned at all times in the beta-2 agonist (S3) category, with a reporting level of 10 ng/mL for the free parent form in urine. Unlike many other stimulants, higenamine is banned both in and out of competition, making it particularly risky for drug-tested athletes.
In 2016, French footballer Mamadou Sakho was temporarily banned by UEFA after testing positive for higenamine, causing the player to miss the 2016 Europa League final. The ban was lifted after the player successfully made the mitigating defence that there was an absence of significant negligence as the substance was not on the list of banned substances despite drugs of the same category — β2 agonists — being banned.
In one study, an investigation into the content of beetroot or beetroot-containing foodstuffs and supplement products was conducted. Higenamine was confirmed as present within the majority of foodstuffs and supplements, with experimental evidence that higenamine can arise within beetroot extracts through heating. This finding indicates a potential for inadvertent doping exposure from common food products, particularly when heated.
DoD Prohibition
Higenamine is on the U.S. Department of Defense (DoD) Prohibited Dietary Supplement Ingredients list.
Regulatory and Legal Status
Higenamine, also known as norcoclaurine HCl, is legal to use within food supplements in the UK, EU, the USA, and Canada — though this legal status applies specifically to its natural presence within botanical ingredients. Its clinical use is limited by the need for further research on its long-term safety, pharmacokinetics, and interactions with other drugs. Despite its promising therapeutic potential, higenamine's inclusion in the World Anti-Doping Agency's banned list highlights concerns over its stimulant effects and safety in athletic contexts.
Known Drug Interactions and Special Populations
Higenamine's clinical use is limited by the need for further research on its pharmacokinetics and interactions with other drugs. Due to its β-adrenergic agonist activity, higenamine would be expected to interact with other adrenergic agents, beta-blockers, and cardiovascular medications. However, specific drug interaction data from human clinical studies is not available in the published literature. Fuzi (the higenamine-containing aconite root preparation) carries toxic metabolites, and the dosage should be carefully adjusted to prevent side effects.
10. Overall Evidence Assessment
Research on the use of higenamine as a drug for the potential treatment of heart disorders (mostly with animals and cells) suggests that it can improve heart function and increase heart rate. The limited and relatively small studies conducted with humans suggest that higenamine, given intravenously, could be useful for emergency cardiac conditions because it can stimulate the heart.
Higenamine has been studied for its potential in weight loss, anti-inflammatory properties, and antioxidant properties, with applications in treating asthma, cardiovascular diseases, and ischemia-reperfusion injuries. However, across nearly all marketed indications — weight loss, athletic performance, and energy enhancement — evidence from human oral supplementation trials is either absent or extremely weak. The body of mechanistic evidence largely derives from animal models and in vitro systems.
The safety and effectiveness of higenamine for any marketed claim are unknown.
References
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