Higenamine is a naturally occurring stimulant found in plants such as Aconitum (carmichaeli and japonicum), Nandina domestica, Nelumbo nucifera, and Sinomenium acutum. It was initially isolated in 1976 from Aconitum, a toxic herb that can cause fatal cardiac poisoning. Today, higenamine can be manufactured (synthesized) as well as extracted from such plants. As a dietary supplement ingredient, it has been marketed in products for weight loss, energy enhancement, and athletic performance. Both natural and synthetic higenamine might promote stimulant effects.

Higenamine is on the FDA Dietary Supplement Ingredient Advisory List because it does not appear to be a lawful ingredient in dietary supplements. The safety of products containing higenamine is unknown.

The World Anti-Doping Agency (WADA) has prohibited the use of higenamine since 2017. The U.S. Food and Drug Administration (FDA) has received reports of adverse effects associated with higenamine-containing dietary supplements since 2014, which led FDA to add higenamine to its Dietary Supplement Ingredient Advisory List, with the statement that it does not appear to be a lawful ingredient in dietary supplements. On 12 March 2021, FDA published an Import Alert that products containing higenamine are considered “adulterated,” and no information provides “reasonable assurance” that this ingredient “does not present a significant or unreasonable risk of illness or injury.” Thus, dietary supplement products with higenamine as an ingredient cannot be imported into the U.S.

What does the science say?

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 (relatively small) studies conducted with humans suggest that higenamine, given intravenously, could be useful for emergency cardiac conditions because it can stimulate the heart. Research also suggests higenamine might have anti-inflammatory effects. Side effects reported include dizziness, nausea, headaches, heart palpitations, and chest pain. In the U.S., FDA has never investigated or approved higenamine for use as a drug for any condition.

How the intravenous doses used in studies translate to oral dose, such as in dietary supplements, is largely unknown. A single small study showed no significant effects on heart rate, breathing, blood pressure, or blood chemistry—either positive or negative—with oral use of up to 150 mg higenamine for 8 weeks. More and larger studies on oral use are needed, but no safe amount has been established. As a result, it is impossible to know if a dietary supplement containing higenamine is safe.

How much higenamine do dietary supplements have?

Dietary supplement products listing higenamine on their Supplement Facts labels often appear as part of a “proprietary blend,” which makes it impossible to determine from the label the exact amount of the ingredient supposedly present. Other label amounts typically range 10–75 mg in a single serving. However, 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 the quantity listed. Some products listing higenamine also contain combinations of other stimulants with unknown effects.

Should Military Service Members avoid the use of supplements with higenamine?

Given the status of higenamine with WADA and FDA, higenamine appears to be unsuitable for use in dietary supplements, so Military Service Members should avoid supplements with this ingredient. Since FDA’s addition of higenamine to its Advisory List, a number of supplements have been reformulated and no longer include higenamine. However, some products tested still contain higenamine, even when it is not listed on product labels. It is important to check for third-party certification seals to ensure what is on the label is actually contained in a product. The safety and effectiveness of higenamine for any marketed claim are unknown. Other common names for higenamine to watch out for include the following:

  • norcoclaurine
  • demethylcoclaurine
  • 1-(4-hydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline-6,7-diol
  • Isoquinolin-6,7-diol, 1,2,3,4-tetrahydro-1-[4-hydroxybenzyl]
  • 6,7-dihydroxy-1-(4-hydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline

Bottom line

Higenamine is currently on the FDA Dietary Supplement Ingredient Advisory List because it does not appear to be a lawful dietary supplement ingredient. It is unknown how products containing higenamine might affect your readiness or health.

 

Posted 11 June 2021

References

Bloomer, R. J., Schriefer, J. M., & Gunnels, T. A. (2015). Clinical safety assessment of oral higenamine supplementation in healthy, young men. Human & Experimental Toxicology, 34(10), 935–945. doi:10.1177/0960327114565490

Calvert, R., Vohra, S., Ferguson, M., & Wiesenfeld, P. (2015). A beating heart cell model to predict cardiotoxicity: Effects of the dietary supplement ingredients higenamine, phenylethylamine, ephedrine and caffeine. Food and Chemical Toxicology, 78, 207–213. doi:10.1016/j.fct.2015.01.022

Cohen, P. A., Travis, J. C., Keizers, P. H. J., Boyer, F. E., & Venhuis, B. J. (2018). The stimulant higenamine in weight loss and sports supplements. Clinical Toxicology, 57(2), 125–130. doi:10.1080/15563650.2018.1497171

Cohen, P. A., Travis, J. C., Vanhee, C., Ohana, D., & Venhuis, B. J. (2021). Nine prohibited stimulants found in sports and weight loss supplements: deterenol, phenpromethamine (Vonedrine), oxilofrine, octodrine, beta-methylphenylethylamine (BMPEA), 1,3-dimethylamylamine (1,3-DMAA), 1,4-dimethylamylamine (1,4-DMAA), 1,3-dimethylbutylamine (1,3-DMBA) and higenamine. Clinical Toxicology, 1–7. doi:10.1080/15563650.2021.1894333

Deldicque, L., & Francaux, M. (2016). Potential harmful effects of dietary supplements in sports medicine. Current Opinion in Clinical Nutrition and Metabolic Care, 19(6), 439–445. doi:10.1097/mco.0000000000000321

Eichner, S., Maguire, M., Shea, L. A., & Fete, M. G. (2016). Banned and discouraged-use ingredients found in weight loss supplements. Journal of the American Pharmacists Association, 56(5), 538–543. doi:10.1016/j.japh.2016.03.013

Feng, S., Jiang, J., Hu, P., Zhang, J.-y., Liu, T., Zhao, Q., & Li, B.-l. (2012). A phase I study on pharmacokinetics and pharmacodynamics of higenamine in healthy Chinese subjects. Acta Pharmacologica Sinica, 33(11), 1353–1358. doi:10.1038/aps.2012.114

Grucza, K., Kowalczyk, K., Wicka, M., Szutowski, M., Bulska, E., & Kwiatkowska, D. (2019). The use of a valid and straightforward method for the identification of higenamine in dietary supplements in view of anti‐doping rule violation cases. Drug Testing and Analysis, 11(6), 912–917. doi:10.1002/dta.2602

Guan, J., Lin, H., Xie, M., Huang, M., Zhang, D., Ma, S., . . . Zhao, G. (2019). Higenamine exerts an antispasmodic effect on cold‑induced vasoconstriction by regulating the PI3K/Akt, ROS/α2C‑AR and PTK9 pathways independently of the AMPK/eNOS/NO axis. Experimental and Therapeutic Medicine, 18, 1299–1308. doi:10.3892/etm.2019.7656

Huang, Y.-F., He, F., Wang, C.-J., Xie, Y., Zhang, Y.-Y., Sang, Z., . . . Zhou, H. (2020). Discovery of chemical markers for improving the quality and safety control of Sinomenium acutum stem by the simultaneous determination of multiple alkaloids using UHPLC-QQQ-MS/MS. Scientific Reports, 10(1), article 14182. doi:10.1038/s41598-020-71133-4

Jeter, J., DeZee, K. J., & Kennedy, L. (2015). A case of paraspinal muscle rhabdomyolysis in a 22-year-old male after ingesting a supplement containing higenamine. Military Medicine, 180(7), e847–e849. doi:10.7205/milmed-d-14-00647

Lee, S.-R., Schriefer, J. M., Gunnels, T. A., Harvey, I. C., & Bloomer, R. J. (2013). Acute oral intake of a higenamine-based dietary supplement increases circulating free fatty acids and energy expenditure in human subjects. Lipids in Health and Disease, 12(1), Article 148. doi:10.1186/1476-511x-12-148

Martínez-Sanz, J., Sospedra, I., Ortiz, C., Baladía, E., Gil-Izquierdo, A., & Ortiz-Moncada, R. (2017). Intended or unintended doping? A review of the presence of doping substances in dietary supplements used in sports. Nutrients, 9(10), Article 1093. doi:10.3390/nu9101093

Okano, M., Sato, M., & Kageyama, S. (2017). Determination of higenamine and coclaurine levels in human urine after the administration of a throat lozenge containing Nandina domestica fruit. Drug Testing and Analysis, 9(11–12), 1788-1793. doi:10.1002/dta.2258

Singhuber, J., Zhu, M., Prinz, S., & Kopp, B. (2009). Aconitum in traditional Chinese medicine—A valuable drug or an unpredictable risk? Journal of Ethnopharmacology, 126(1), 18–30. doi:10.1016/j.jep.2009.07.031

Stajić, A., Anđelković, M., Dikić, N., Rašić, J., Vukašinović-Vesić, M., Ivanović, D., & Jančić-Stojanović, B. (2017). Determination of higenamine in dietary supplements by UHPLC/MS/MS method. Journal of Pharmaceutical and Biomedical Analysis, 146, 48–52. doi:10.1016/j.jpba.2017.08.017

Xie, Y., Li, X., Chen, J., Deng, Y., Lu, W., & Chen, D. (2018). pH effect and chemical mechanisms of antioxidant higenamine. Molecules, 23(9), Article 2176. doi:10.3390/molecules23092176

Yang, X., Liu, N., Li, X., Yang, Y., Wang, X., Li, L., . . . Shang, H. (2018). A review on the effect of traditional Chinese medicine against anthracycline-induced cardiac toxicity. Frontiers in Pharmacology, 9, Article 444. doi:10.3389/fphar.2018.00444

Zhang, N., Lian, Z., Peng, X., Li, Z., & Zhu, H. (2017). Applications of higenamine in pharmacology and medicine. Journal of Ethnopharmacology, 196, 242–252. doi:10.1016/j.jep.2016.12.033

Zhang, Y., Zhang, J., Wu, C., Guo, S., Su, J., Zhao, W., & Xing, H. (2018). Higenamine protects neuronal cells from oxygen‐glucose deprivation/reoxygenation‐induced injury. Journal of Cellular Biochemistry, 120(3), 3757–3764. doi:10.1002/jcb.27656