Benefits
May support lipolysis and calorie burn, but only tested inside a stimulant blend
In a crossover study of 16 young adults, one dose of a product combining higenamine with 270 mg of caffeine and yohimbe bark extract raised blood free fatty acids and calories burned, by roughly 10 kcal an hour, over three hours versus placebo. The higenamine amount was not disclosed, the work was part-funded by the supplement company USPlabs, and caffeine and yohimbine drive fat release on their own.
Body fat and resting metabolism with higenamine alone
The only efficacy trial of higenamine by itself gave 75 mg a day to six recreational female basketball players, with six others on placebo, for three weeks. Body fat, resting metabolic rate and blood free fatty acids did not change compared with placebo. The trial was tiny and short, but it is the only direct test of the fat-loss claim, and it found nothing to support it.
Exercise performance and endurance claims lack human support
Higenamine is sold in pre-workouts because it behaves like a beta-2 agonist, the drug class of asthma inhalers. In the same three-week trial, maximal oxygen uptake, peak heart rate, heart-rate recovery and heart function on echocardiography did not change versus placebo. We found no human trial showing better strength, power, endurance or sprint output.
Prohibited in sport at all times and for US service members
The World Anti-Doping Agency lists higenamine among the beta-2 agonists banned both in and out of competition, and the US Department of Defense lists it as a prohibited supplement ingredient. Because it occurs in lotus plumule, Nandina and aconite, products can contain it under a plant name or a synonym such as norcoclaurine.
A cardiac stimulant developed in China as a heart stress-test drug
Higenamine was first isolated as the heart-stimulating compound in aconite root. An intravenous form was taken through phase III trials in China as a pharmacologic stress agent for heart imaging, and in volunteers intravenous doses raised heart rate in step with blood levels. That is drug research on the heart, not evidence of a supplement benefit.
Mechanism of action
Beta-1 and beta-2 adrenergic receptor agonism
Higenamine activates beta-1 receptors, which speed and strengthen the heartbeat, and beta-2 receptors, which relax airway and vascular smooth muscle. A receptor-modelling study found it far more potent at the heart's beta-1 receptor than at beta-2, so heart effects are the expected result of an active dose.
Beta-adrenergic fat release
Beta-adrenergic stimulation raises cyclic AMP in fat cells and switches on the enzymes that release stored fatty acids into the blood. That is the rationale for fat-burner use, but a short rise in circulating free fatty acids is not the same as losing body fat; released fatty acids still have to be burned for fat stores to shrink.
Very short half-life and uncertain oral absorption
Given intravenously to volunteers, higenamine cleared from the blood with a half-life of about 8 minutes. Oral absorption appears poor: rabbit and rat studies found low bioavailability, and human oral data are scarce. Even so, pharmacokinetic modelling predicted that amounts found in supplements can reach levels that activate heart beta-1 receptors.
Stacked with other stimulants
Products usually pair higenamine with caffeine, yohimbine or other stimulant amines. In the blend study, systolic blood pressure rose about 12 mmHg and heart rate about 3 beats per minute from pre-dose values, and the authors attributed most of that to the caffeine and yohimbe rather than to higenamine.
Clinical trials
Randomized, double-blind, placebo-controlled crossover study of a single dose of a higenamine-based supplement (Lee SR, Schriefer JM, Gunnels TA, Harvey IC, Bloomer RJ 2013, Lipids Health Dis 12:148, PMID 24139127). Funded in part by USPlabs, LLC.
16 healthy, active young adults (8 men, 8 women), tested after an overnight fast.
Compared with placebo, the blend raised plasma free fatty acids and calorie expenditure (about 10 kcal per hour more) at 60, 120 and 180 minutes, while glycerol and respiratory exchange ratio did not change. Heart rate rose about 3 bpm and systolic blood pressure about 12 mmHg from pre-dose values. The product also held 270 mg of caffeine plus yohimbe, the higenamine dose was not disclosed, and the authors said they could not separate each ingredient's contribution.
Randomized, double-blind, placebo-controlled safety study of higenamine alone, caffeine alone, or higenamine with caffeine and yohimbe bark extract (Bloomer RJ, Schriefer JM, Gunnels TA 2015, Hum Exp Toxicol 34(10):935-45, PMID 25591969). Funded in part by USPlabs, LLC.
48 healthy young men, 12 per group; 50 mg higenamine capsules taken one to three times daily for 8 weeks.
Resting heart rate, blood pressure, breathing rate, urinalysis, blood counts, metabolic panel, liver enzymes and lipids did not change in any group. With 12 men per arm the study could only detect large, common harms, it measured nothing about fat loss or performance, and one man in the combination group, who said he had accidentally taken a double dose, reported a rapid heart rate, poor appetite and trouble sleeping in the first days.
Randomized, double-blind, placebo-controlled trial of a single-ingredient higenamine supplement, 25 mg three times daily (Rasic JS, Ivanovic ND, Andjelkovic MS, et al. 2021, Front Psychol 12:633110, PMID 34557123). The authors declared no commercial conflicts.
12 recreational female basketball players aged 29 to 41, six on higenamine and six on placebo, for 21 days.
Body fat, resting metabolic rate, free fatty acids, maximal oxygen uptake, peak heart rate, heart-rate recovery and echocardiographic heart function did not differ from placebo, and safety labs stayed stable. Four of six women on higenamine reported transient headache or dry mouth, against two of six on placebo with headache. The authors concluded that 75 mg a day did not improve fitness or produce weight loss.
Independent laboratory analysis of US supplements labeled as containing higenamine or a synonym, tested by NSF International and the Dutch National Institute for Public Health and the Environment (Cohen PA, Travis JC, Keizers PHJ, Boyer FE, Venhuis BJ 2019, Clin Toxicol (Phila) 57(2):125-130, PMID 30188222).
24 supplement brands on sale before the WADA prohibition, 46% marketed for weight loss and 46% for sports or energy.
Higenamine ranged from trace amounts to 62 mg per serving, and following label directions could deliver up to 110 mg a day. Of the five products that stated an amount, none was accurate: actual content ran from under 0.01% to 200% of the label. A buyer cannot know how much they are taking.
Phase I pharmacokinetic and pharmacodynamic study of escalating intravenous infusions from 0.5 to 4.0 mcg/kg/min, each for 3 minutes (Feng S, Jiang J, Hu P, Zhang JY, Liu T, Zhao Q, Li BL 2012, Acta Pharmacol Sin 33(11):1353-8, PMID 23085737).
10 healthy Chinese volunteers.
Higenamine cleared with a half-life of about 8 minutes (0.133 h), about 9% was recovered in urine within 8 hours, and heart rate rose in direct relation to plasma concentration. This is the drug research behind its use as a cardiac stress agent; it used injection rather than oral supplements and shows a direct, concentration-linked rise in heart rate.