Supplements

Higenamine

Updated · 27 sources

Higenamine, also called norcoclaurine or demethylcoclaurine, is a plant alkaloid that stimulates beta-adrenergic receptors, the same receptor family targeted by albuterol and clenbuterol. It raises heart rate and the force of heart contraction. It has been sold in US “fat burner” and pre-workout supplements, often alongside caffeine, and has been tested in blends with yohimbe, the plant source of yohimbine.

Three facts define its status. The World Anti-Doping Agency (WADA) has prohibited it at all times since 2017. The FDA treats supplements containing it as adulterated and has cited its “potential for serious cardiotoxic effects.” And in China, an injectable form was approved in 2026 as a cardiac stress-test drug, a use unrelated to fat loss or performance. The controlled oral evidence is limited to three small studies, and none shows that higenamine itself causes fat loss or improves performance.

This page summarizes what the clinical studies, anti-doping laboratories and regulators report. It is for education only and is not medical advice.

Property Detail
Class Benzylisoquinoline alkaloid; beta-adrenergic agonist
Other names Norcoclaurine, demethylcoclaurine
Formula C₁₆H₁₇NO₃; relative molecular mass 271.3
Plant sources Aconitum (aconite), lotus plumule, Nandina domestica, Tinospora crispa, Annona fruit and others
Approved medical use China only (2026): injection for stress myocardial perfusion imaging; 2.5 mg per 2 mL in the marketing application
Oral doses studied 75 mg/day for 21 days; capsules of 50 mg for 8 weeks; undisclosed amounts in a blend
Half-life ≈8 min in plasma after IV dosing (0.133 h); 4–27 h estimated from urine after oral dosing
US status No FDA-approved drug found; FDA considers supplements containing it adulterated
WADA status Prohibited at all times; S3 beta-2 agonists; Specified Substance; no exception for higenamine

What it is

Higenamine was first isolated from Aconitum root in 1976 and identified as a heart-stimulating compound. Its structure resembles the catecholamines, the family that includes adrenaline (Wen et al., Front Pharmacol 2022).

A 2022 review lists these plants as containing it: Nelumbo nucifera (lotus), Tinospora crispa, Nandina domestica, Gnetum parvifolium, two Asarum species, Aconitum carmichaelii and Aristolochia brasiliensis (Kozhuharov et al., Plants 2022). In supplements it can come from a botanical ingredient or be added as a synthetic compound, often in milligram amounts (Leaney et al., Drug Test Anal 2023). The Chinese injection is made by chemical synthesis (Rundu filing, 2024).

Receptor activity

Most of the receptor data come from cells and isolated tissue:

  • Beta-2. In cells expressing human beta-2 receptors, higenamine had a potency of 230 nM and behaved as a near-full agonist, with over 80% of the maximum effect of adrenaline. An earlier study summarized in the same paper found it about 10-fold less potent than salbutamol (albuterol) (Hudzik et al., Drug Test Anal 2021).
  • Beta-1. It is generally described as a non-selective beta agonist. Beta-1 activity explains the rise in heart rate and contractility (Wen et al. 2022).
  • Alpha. Findings are less settled. The same review describes activation of alpha receptors and also reports that higenamine was identified as an alpha-1 antagonist, which may help explain its blood pressure-lowering effect in some models.

Sources also differ on how to label it. The Chinese manufacturer calls it a partial beta agonist, while the human beta-2 cell assay above found near-full agonism. Higenamine’s effects should therefore not be assumed to match those of a selective beta-2 drug.

Pharmacokinetics

The main published human plasma data come from a phase I study in 10 healthy Chinese volunteers. They received an IV infusion escalating from 0.5 to 4.0 μg/kg/min, with each step lasting 3 minutes (Feng et al., Acta Pharmacol Sin 2012). One author was affiliated with Zhuhai Rundu Pharmaceutical, the company that later obtained approval in China.

Parameter Result (IV, healthy adults)
Peak concentration 15.1–44.0 ng/mL
Half-life 0.133 h, or ≈8 min (range 0.107–0.166 h)
Volume of distribution 48 L (range 30.8–80.6 L)
Total clearance 249 L/h (range 199–336 L/h)
Unchanged drug in urine within 8 h 9.3% (range 4.6%–12.4%)
Heart rate model Baseline 68 bpm; maximum drug effect (Emax) 73 bpm; half-maximal effect at 8.1 μg/L

Why two very different half-lives appear

The 8-minute value and the 4–27 hour value measure different things. The first is plasma elimination after a brief IV infusion. The second comes from a study of female basketball players taking repeated oral capsules, and it was estimated from urine with large differences between individuals. Urine concentrations stayed above 10 ng/mL for at least 20 hours after the last dose in all participants (Stojanovic et al., J Chromatogr B 2024).

Oral absorption is poorly defined

Human oral plasma data are scarce. Rabbit and rat studies suggest very low oral bioavailability, and no study allows direct comparison of oral and IV doses in people (Rasic et al., Front Psychol 2021). Even so, small oral amounts clearly reach the urine, which led Food Standards Australia New Zealand (FSANZ) to conclude that higenamine is orally bioavailable (FSANZ 2021).

A 2025 computer-modeling study extrapolated cell data to whole-body doses. It predicted that reported supplement intakes reach or exceed the doses needed to activate adrenergic receptors, and it named higenamine a high priority for risk assessment (Pinckaers et al., Arch Toxicol 2025). This is a prediction, not a measurement in people.

Medical use: IV cardiac stress testing in China

Pharmacologic stress testing uses a drug to mimic the effect of exercise on the heart in patients having heart imaging. Chinese researchers have studied IV higenamine for this purpose and for slow heart rhythms since at least 1980. One review collects these human studies (Wen et al. 2022):

Population n Regimen Reported effect
Healthy volunteers (phase I) 10 Infusion escalating from 0.5 to 4 μg/kg/min Heart rate up; diastolic pressure down
Healthy volunteers (tolerability) 32 Same escalating infusion Heart rate up; diastolic pressure down
Confirmed or suspected heart disease 120 Same escalating infusion Heart rate up; diastolic pressure down
Suspected heart disease 71 Same escalating infusion Heart rate up; diastolic pressure down
Heart block 68 2.5 mg slow IV infusion Heart rate up; blood pressure variable
Sick sinus syndrome 22 2.5 mg slow IV infusion Heart rate up
Heart disease (left ventricular function) 19 2.5 mg slow IV infusion Heart rate and cardiac output up

The review’s table prints these infusion rates in mg/kg/min, but the phase I paper it cites reports μg/kg/min, so μg is shown here.

In a randomized, single-blind Beijing study, higenamine injection was compared with adenosine, using coronary angiography as the reference. The abstract reports no statistically significant difference in efficacy or safety, but it does not give patient numbers or accuracy figures (Tian et al., Chin J Clin Pharmacol 2012).

The manufacturer’s 2024 filing describes a multicenter, randomized phase IIIb crossover trial with an active control, led by Peking Union Medical College Hospital. The company says adverse reactions were mild and resolved quickly after the infusion stopped, but the filing gives no numbers (Rundu filing, 2024). In April 2026 the company announced that China’s National Medical Products Administration had issued a registration certificate. It describes the product as the only beta-agonist stress agent for myocardial perfusion imaging approved in China (Yicai, 2026). We relied on the company’s statements and did not find published phase III accuracy data.

This approval does not support supplement use. It covers a small, monitored IV dose given in a clinical setting to assess the heart. The strength in the marketing application was 2.5 mg per 2 mL, while supplements tested in the US contained up to 62 mg per serving by mouth. The two routes cannot be compared directly, since no oral-to-IV equivalence has been established.

What the research shows

Fat loss and performance

Only three controlled human studies of oral higenamine turned up, and they answer different questions:

Study Who What was given Result
Lee et al., Lipids Health Dis 2013 16 healthy young adults (8 men, 8 women); double-blind crossover Single dose of a blend: higenamine (amount undisclosed), caffeine 270 mg, yohimbe extract; or placebo Free fatty acids and calorie burn higher over 3 hours (≈10 kcal/hour above placebo). Glycerol and fuel use (RER) unchanged. Heart rate up ≈3 bpm; systolic pressure up ≈12 mmHg
Bloomer et al., Hum Exp Toxicol 2015 48 men, divided among 4 arms Placebo, higenamine, caffeine, or higenamine plus caffeine plus yohimbe, daily for 8 weeks Safety study. No significant changes in vital signs, blood counts, liver enzymes, metabolic panel or lipids. Fat loss and performance were not its stated outcomes
Rasic et al., Front Psychol 2021 12 recreational female basketball players aged 29–41 (14 randomized); 6 per group Higenamine 75 mg/day in 3 doses, or placebo, for 21 days No difference in body fat (p = 0.223), resting metabolic rate (p = 0.169), free fatty acids (p = 0.206) or exercise testing

Several limits apply:

  • Lee 2013 cannot isolate higenamine. Caffeine and yohimbine affect fat release and calorie burn on their own. The authors acknowledge that their design could not separate the three ingredients, and the work was funded in part by USPlabs, a supplement company. The supplement’s weight-loss effect was not measured.
  • Rasic 2021 is the only trial of higenamine alone that measured fat loss and performance, but it is very small. The authors state that 6 people per group was too few for some outcomes. Their suggestion that higenamine shows no beta-agonist activity at this dose goes further than a trial of this size can establish, and it applies only to the women studied.
  • Bloomer 2015 is a safety study. The dose per capsule (50 mg) comes from a later review; the abstract does not state the dose.

We found no controlled trial showing that higenamine alone produces fat loss, builds muscle or improves exercise performance in people. The idea that it works “like clenbuterol” rests on receptor pharmacology, not on outcome data. For related stimulant pages, see caffeine, ephedrine and yohimbine.

Other proposed uses

Reviews describe heart-protective, anti-fibrotic and antioxidant effects (Wen et al. 2022). Most of this work is in cells or animals, and the bronchodilator effects have been shown only in non-human models (Rasic et al. 2021). These findings do not establish benefit in people.

Label accuracy and product quality

The main US market analysis tested all 24 supplements identified as listing higenamine or a synonym, before WADA’s prohibition took effect (Cohen et al., Clin Toxicol 2019):

  • 11 of 24 products (46%) were marketed for weight loss and another 11 (46%) for sports or energy.
  • Higenamine ranged from trace amounts to 62 ± 6.0 mg per serving.
  • Following label directions could mean up to 110 ± 11 mg/day.
  • Only 5 of 24 products (21%) stated an amount, and none of those 5 was accurate. Actual content ranged from under 0.01% to 200% of the stated quantity.

Other reports point the same way. A 2018 Australian laboratory survey cited by FSANZ found higenamine in 10% of randomly selected pre-workout or fat-burner supplements, and FSANZ warns that products may not state the amount (FSANZ 2021). As a result, the amount in a given product cannot be judged from its label. DMHA is another stimulant in this product category with its own page.

Side effects and risks

Cardiovascular effects

Heart rate rose consistently in the IV studies, with variable effects on blood pressure. Reported adverse reactions with IV use include shortness of breath, palpitations, dizziness, headache and chest tightness (Wen et al. 2022). Those effects occurred under medical supervision and with short infusions, so they do not establish a safe oral dose.

Oral data are reassuring only within narrow limits. The Bloomer and Rasic trials enrolled 60 healthy participants across all arms, only some of whom took higenamine, for at most 8 weeks. They were not sized to detect rare cardiac events. In Rasic, 4 of 6 women taking higenamine reported temporary symptoms (headache in 3, dry mouth in 1), compared with headache in 2 of 6 on placebo. The authors’ description of the dose as “safe” should be read with that sample size in mind. FSANZ concluded that higenamine has not been adequately tested for safety, particularly by mouth, and that thresholds for harm from oral exposure cannot be determined (FSANZ 2021).

Preclinical findings

These results come from laboratory systems and cannot be applied directly to people:

  • Human heart cell line. Higenamine at 31.3 and 313 ng/mL raised the beating rate, and adding caffeine increased it further. The combination is relevant because caffeine often accompanies higenamine in products. The work was done by FDA scientists (Calvert et al., Food Chem Toxicol 2015).
  • Rats. In conscious rats given rising IV doses, higenamine raised heart rate by up to 110 bpm. The authors warn that such compounds could add to cardiovascular strain during exercise (Pinckaers et al., Eur J Pharmacol 2026).
  • Mice. The reported median lethal dose was 58.9 mg/kg IV, 300 mg/kg into the abdominal cavity and 3.35 g/kg by mouth (Wen et al. 2022).
  • Chromosome damage in cell culture. A 2026 study in cultured V79 cells found chromosome damage (micronuclei) at 300–510 μM but no gene mutations at the locus tested. This is the first evidence of its kind. The concentrations are high compared with the ng/mL levels measured in human plasma, and we found no animal or human follow-up (Veh et al., Toxicol Lett 2026).

Case reports

A 22-year-old man developed rhabdomyolysis (muscle breakdown) of the back muscles, with possible compartment syndrome, after strenuous activity and use of an exercise supplement containing higenamine. His kidneys were not damaged, but he had pain for the next 4 months (Jeter et al., Mil Med 2015). Strenuous exercise and the other contents of the product may have contributed, so one case cannot establish cause. FSANZ’s literature search to February 2020 found only this case, and our PubMed search found no other case report naming higenamine. A short list of published cases does not show that higenamine is safe.

Plant source and interactions

  • Aconite. Aconitum plants are toxic and can cause fatal heart poisoning (OPSS, 2022). In isolated mouse heart tissue, higenamine enhanced the fast heart rhythm caused by aconitine (Wen et al. 2022).
  • Stimulant combinations. FSANZ notes that higenamine is often combined with other substances that affect blood pressure, such as caffeine, and that the effects of these mixtures are unknown.
  • Bleeding. Higenamine inhibits platelet aggregation in laboratory work. FSANZ says this might raise bleeding risk in people with clotting disorders, those on anticoagulants or people scheduled for surgery.
  • Drug metabolism. FSANZ also notes that it inhibits some liver enzymes and might alter the metabolism of prescribed drugs. No human interaction study was found.
  • Higher-risk groups. FSANZ considers people with existing heart rate or blood pressure disorders to be at greatest risk.

Regulatory status

United States

The FDA has taken these positions:

  • September 2021. A warning letter said higenamine is a new dietary ingredient lacking evidence of safety, that products containing it are adulterated, and that “the available evidence underscores higenamine’s potential for serious cardiotoxic effects” (FDA warning letter, Condemned Labz, 2021).
  • May 2022. A further round of letters used two legal theories. Higenamine, as a constituent of aconite, asarum, lotus and other botanicals, is a new dietary ingredient for which FDA has received no safety notification. Higenamine HCl is not a dietary ingredient at all and is considered an unsafe food additive (FDA warning letter, Steel Supplements, 2022).
  • Import controls. Import Alert 54-18 allows detention of dietary supplements and bulk ingredients containing new dietary ingredients with inadequate safety information. Higenamine appears in the product descriptions of some listed firms on the version dated June 27, 2025 (FDA Import Alert 54-18).
  • Advisory list. FSANZ reports that higenamine was on FDA’s Dietary Supplement Ingredient Advisory List from its start in April 2019 (FSANZ 2021). We could not open the current version of that list.

We found no higenamine-specific rule or ban. FDA’s position has been applied through warning letters and import controls, so products may still appear on the market.

The US Department of Defense also includes higenamine on its Prohibited Dietary Supplement Ingredients list, per an Operation Supplement Safety page last updated in March 2022 (OPSS, 2022).

Australia

FSANZ’s imported food risk statement, last updated in December 2021, says higenamine has no history of safe use as a food in Australia and is not explicitly permitted as a novel food. At that date it was not scheduled by the Therapeutic Goods Administration (FSANZ 2021).

China

See the section above on IV stress testing. The approval covers the injection only.

Anti-doping and food sources

How WADA classifies it

The WADA 2026 Prohibited List names higenamine under S3, beta-2 agonists:

  • It is prohibited at all times, in and out of competition.
  • All substances in S3 are Specified Substances.
  • S3’s dose exceptions cover only inhaled salbutamol, formoterol, salmeterol and vilanterol. Higenamine has no exception.

Separately, anti-doping laboratories describe a minimum reporting level of 10 ng/mL for free (unconjugated) higenamine in urine (Leaney et al. 2023). This is a reporting rule. It is not a permitted amount, and it does not mean that intake is allowed. We could not open WADA’s current technical document directly, so this figure is taken from the laboratory literature.

Higenamine accounted for 46 adverse analytical findings in 2019, or 30% of the S3 total (Leaney et al. 2023). A review citing a 2020 WADA report gives 26 findings, second among beta-2 agonists. It does not state the testing year, so the two counts may not be comparable. The same review reports US sanctions of 10 to 20 months in cases linked to supplements (Kozhuharov et al. 2022).

Which foods and herbs can cause a positive test

Risk depends heavily on the source and the amount consumed:

Source Study Urine finding Exceeded 10 ng/mL?
Lotus plumule capsules Yan et al., Drug Test Anal 2019: 14 volunteers, 6 capsules of 0.34 g daily for 7 days Maximum 500 ng/mL Yes, high risk
Higenamine tablets Yan et al. 2019: 11 volunteers, three 5 mg tablets daily for 7 days Above the limit in most sample groups during dosing Yes
Annona fruit (A. muricata, A. cherimola, A. squamosa) Rubio et al., Drug Test Anal 2023: single and repeated servings Peak 7.8 ng/mL after single servings; levels built up with repeated intake No, but repeated intake raises the risk
Beetroot drinks Leaney et al. 2023: 6 people Under 1% of the reporting level No, low risk

Other findings add to the picture:

  • Beetroot. Higenamine was found in most beetroot foods and supplements tested, and heating beetroot extract may generate it.
  • Herbal medicines. In 128 Japanese Kampo extract products, 14 crude drugs contained higenamine, its relative coclaurine, or both. Coclaurine is not on the prohibited list, but human liver microsomes (liver enzyme preparations) converted it to higenamine, which raises a further possible route to a positive test (Sakamoto et al., J Nat Med 2025).
  • Telling sources apart. After Annona fruit, a urinary pattern of isococlaurine, reticuline and a methylated higenamine glucuronide appeared that was not seen after supplements. These markers may eventually help separate dietary and supplement sources, but they are not an established defense (Rubio et al. 2023).

Key takeaways

  • No proven fat-loss or performance benefit. The only trial of higenamine alone that tested these outcomes (n = 12) found no effect, and the positive 2013 study used a blend with caffeine and yohimbe.
  • It acts on the heart. IV higenamine reliably raises heart rate, which is why China approved an injectable form in 2026 for cardiac stress imaging. That approval does not apply to oral supplements.
  • FDA considers supplements adulterated. Warning letters cite a lack of safety evidence and its potential for serious cardiotoxic effects.
  • Labels cannot be trusted. In the main US analysis, amounts reached 62 mg per serving, and none of the 5 products stating a quantity was accurate.
  • Oral safety is largely unknown. Small trials in healthy adults found no significant changes in routine measures, but they cannot rule out rare or serious events, and thresholds for harm have not been defined.
  • Prohibited at all times in sport. It sits in WADA class S3 with no exception. Lotus plumule products can far exceed the 10 ng/mL reporting level, while Annona fruit and beetroot produced lower urine levels in the studies so far.

Sources

  1. World Anti-Doping Agency. The 2026 Prohibited List. WADA 2026 Prohibited List.
  2. US Food and Drug Administration. Warning letter: Supplement Science Corp. d/b/a Condemned Labz, MARCS-CMS 613165. September 22, 2021. FDA.
  3. US Food and Drug Administration. Warning letter: Steel Supplements Inc, MARCS-CMS 622405. May 4, 2022. FDA.
  4. US Food and Drug Administration. Import Alert 54-18. Published June 27, 2025. FDA.
  5. Operation Supplement Safety, US Department of Defense. Higenamine in dietary supplements. Updated March 7, 2022. OPSS.
  6. Food Standards Australia New Zealand. Imported food risk statement: supplementary sports foods and higenamine. Compiled July 2020, updated December 2021. FSANZ.
  7. Zhuhai Rundu Pharmaceutical Co., Ltd. Announcement on acceptance of the marketing application for higenamine hydrochloride injection, No. 2024-011 [in Chinese]. March 4, 2024. Shenzhen Stock Exchange.
  8. Yicai. Rundu Pharmaceutical receives drug registration certificate for higenamine hydrochloride injection [in Chinese]. April 3, 2026. Yicai.
  9. Feng S, Jiang J, Hu P, et al. A phase I study on pharmacokinetics and pharmacodynamics of higenamine in healthy Chinese subjects. Acta Pharmacol Sin. 2012;33(11):1353–1358. PubMed.
  10. Wen J, Li M, Zhang W, et al. Role of higenamine in heart diseases: a mini-review. Front Pharmacol. 2022;12:798495. PubMed.
  11. Hudzik TJ, Patel M, Brown A. β2-adrenoceptor agonist activity of higenamine. Drug Test Anal. 2021;13(2):261–267. PubMed.
  12. Tian R, Wang Q, Mi H, et al. Efficacy and safety of higenamine hydrochloride injection used in pharmacologic stress myocardial perfusion imaging [in Chinese]. Chin J Clin Pharmacol. 2012;28(2):88–90. NAPSTIC.
  13. Lee SR, Schriefer JM, Gunnels TA, et al. Acute oral intake of a higenamine-based dietary supplement increases circulating free fatty acids and energy expenditure in human subjects. Lipids Health Dis. 2013;12:148. PubMed.
  14. Bloomer RJ, Schriefer JM, Gunnels TA. Clinical safety assessment of oral higenamine supplementation in healthy, young men. Hum Exp Toxicol. 2015;34(10):935–945. PubMed.
  15. Rasic JS, Ivanovic ND, Andjelkovic MS, et al. Influence of higenamine on exercise performance of recreational female athletes: a randomized double-blinded placebo-controlled trial. Front Psychol. 2021;12:633110. PubMed.
  16. Cohen PA, Travis JC, Keizers PHJ, et al. The stimulant higenamine in weight loss and sports supplements. Clin Toxicol (Phila). 2019;57(2):125–130. PubMed.
  17. Pinckaers NET, Blankesteijn WM, Mircheva A, et al. Quantitative in vitro-to-in vivo extrapolation of human adrenergic and trace amine-associated receptor 1 potencies of pre-workout supplement ingredients using physiologically based kinetic modelling-based reverse dosimetry. Arch Toxicol. 2025;99(5):1999–2021. PubMed.
  18. Pinckaers NET, Blankesteijn WM, Peeters R, et al. Phenethylamines in pre-workout supplements alter arterial pressure, heart rate, and body temperature in rats. Eur J Pharmacol. 2026;1026:178966. PubMed.
  19. Calvert R, Vohra S, Ferguson M, et al. A beating heart cell model to predict cardiotoxicity: effects of the dietary supplement ingredients higenamine, phenylethylamine, ephedrine and caffeine. Food Chem Toxicol. 2015;78:207–213. PubMed.
  20. Veh EM, Wenninger P, Fleischmann E, et al. Clastogenicity of the food constituent higenamine in cultured V79 cells. Toxicol Lett. 2026;424:113179. PubMed.
  21. Jeter J, DeZee KJ, Kennedy L. A case of paraspinal muscle rhabdomyolysis in a 22-year-old male after ingesting a supplement containing higenamine. Mil Med. 2015;180(7):e847–e849. PubMed.
  22. Rangelov Kozhuharov V, Ivanov K, Ivanova S. Higenamine in plants as a source of unintentional doping. Plants (Basel). 2022;11(3):354. PubMed.
  23. Stojanovic B, Rasic J, Andjelkovic M, et al. Urinary excretion profile of higenamine in females after oral administration of supplements - doping scenario. J Chromatogr B Analyt Technol Biomed Life Sci. 2024;1235:124047. PubMed.
  24. Yan K, Wang X, Wang Z, et al. The risk of higenamine adverse analytical findings following oral administration of plumula nelumbinis capsules. Drug Test Anal. 2019;11(11-12):1731–1736. PubMed.
  25. Rubio A, Thomas A, Euler L, et al. Investigations into Annona fruit consumption as a potential source of dietary higenamine intake in the context of sports drug testing. Drug Test Anal. 2023;15(11-12):1488–1502. PubMed.
  26. Leaney AE, Heath J, Midforth E, et al. Presence of higenamine in beetroot containing ‘foodstuffs’ and the implication for WADA-relevant anti-doping testing. Drug Test Anal. 2023;15(2):173–180. PubMed.
  27. Sakamoto S, Osaki K, Abe H, et al. Metabolism of coclaurine into the WADA-banned substance higenamine: a doping-relevant analytical evaluation of Kampo extracts. J Nat Med. 2025;79(5):1140–1153. PubMed.