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Higenamine (Norcoclaurine) is part of the Nandina plant that has traditionally been used as an anti-asthmatic and is currently used as a fat burner due to sharing similar mechanisms to ephedrine; limited evidence on these claims.

Our evidence-based analysis on higenamine features 38 unique references to scientific papers.

Research analysis led by and reviewed by the Examine team.
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Research Breakdown on Higenamine

1Sources and Structure


Higenamine (Norcoclaurine) is a benzyltetrahydroisoquinoline[1] that is found in a variety of plants, and seems to be in relatively high concentrations in the fruits of Nandina domestica Thunberg of the Berberidaceae family.

Known plants to possess a Higenamine content are:

A constituent of a variety of plants, rather than a single isolated plant

1.2Structure and Properties

Higenamine, also known as norcoclaurine, is known as a benzyltetrahydroisoquinoline.[1]

It is found in ethanol extracts of the plant rather than water extracts alongside the related compound Nantenine.[2] When the extract was divided into 12 sub fragments to isolate the plant compounds, the fragment that contained higenamine (at 49%) was as potent as the plant itself on tracheal relaxation.[2] Despite the ethanol extract above, the structure is highly polar. Higenamine is unstable in basic solution,[11] and has a molecular weight of 271.31g/mol.



Following an IV injection of Higenamine in healthy volunteers at 0.5-4mcg/mL/min (total doses of 0.2, 4, and 40ng/mL), the AUC was determined to be 5.39ng/h/mL with a half-life of 0.133 hours, and 9.3% of the injected solution was found in the urine after 8 hours.[11] This study is duplicated in Medline,[12] and a similarly short half life has been noted in rabbits either injected or fed Higenamine (50mg/kg bodyweight).[13][14]

The only oral study currently conducted is in rabbits, where 50mg/kg showed high variance in bioavailability and serum concentrations despite hitting similar Tmax values 7.8-8.3 minutes after gastric intubation.[13][14]

When divided into two apparently different groups, the bioavailability was either 2.84+/-0.82% or 21.86+/-2.21% and the serum Cmax values of these groups were (respectively) 0.33+/-0.09mcg/mL and 2.90+/-0.51mcg/mL; both groups attenuating to 20ng/mL after 2 hours.[13][14] These values are for total Higenamine, and serum binding to protein appears to hold static at around 54.8%,[13][14] and an injection of 20mg/kg Higenamine to rabbits appears to correlate very well to oral administration of 50mg/kg.[13][13][14]

Differences in serum values may be mediated at the level of either intestinal absorption or conjugation, and the main conjugative metabolite appears to be via glucuronidation (as assessed by urinary recovery).[13][14]

Minimal pharmacokinetic data at this moment in time, but Higenamine appears to exert a very rapid absorption phase with a very rapid half-life as well. There appears to be a degree of inter-individual difference in how much Higenamine gets into the blood, which may be mediated by Glucuronidation enzymes (possible synergism with Piperidine from Black Pepper if this is the case)

2.2Receptor Interactions

The EC50 value of Higenamine in trachea cells is 47.6+/-1.8ng/mL when looking at a fragment of 49% higenamine extracted from Nandina.[2] although a molar value of 86.0+/-3.3nM was found when looking at Higenamine in isolation; giving Higenamine itself an EC50 of 23.33ng/mL.[2] Synthetic Higenamine appears to have slightly higher EC50 than does that derived from Nandina.[2]

The IC50 value on RAW 264.7 cells (an experimental mouse line of leukocyte immune cells) was 53uM after a 10mg/kg bodyweight I.P injection.[7]



A concentration of 10uM Higenamine in motor neurons isolated form mice (in vitro study) appear to enhance acetylcholine release, and are blocked by propanolol (thus mediated via Beta(2)adrenergic agonism, a known mechanism of Higenamine).[15] Concentrations of 30-100uM Higenamine diminished the ability of motor neurons to release acetylcholine when stimulated, suggesting peak efficacy in the 10-30uM range.[15] Spontaneous release of acetylcholine (without nerve stimulation) was slightly increased.

Possesses possible benefits to muscular output (via increasing acetylcholine release from motor neurons), but no in vivo evidence to assess potency nor optimal dose; mechanism is via beta(2)adrenergic activation


At a concentration of 20mM, Higenamine has been shown in vitro to deplete dopamine concentrations in PC12 neuronal cells by 55.2% with an IC50 of 18.2mM;[16] this was thought to be through inhibition of tyrosine hydroxylase, which converts L-DOPA into dopamine.[17]

May inhibit tyrosine hydroxylase and suppress dopamine, but no in vivo evidence exists


In a rat model of MCAO injury (middle cerebral artery occlusion), 10mg/kg Higenamine (not disclosed whether oral or intracerebral) significantly reduce the infarct size suggesting neuroprotective effects under periods of ischemia.[18]

In vitro, it appears Higenamine increases cell viability in a concentration dependent manner up to 10uM where it stabilizes (higher concentrations not being more effective) which may have been secondary to Higenamine inducing expression of HO-1 (Heme-Oxygenase 1; an anti-oxidant protein which downregulates the proinflammatory HMGB1) at concentrations of 10uM or higher in normoxia and only requiring 1uM in periods of hypoxia.[18] In C6 cells (glial cells), Higenamine induced phosphorylation of PI3K/Akt in a concentration dependent manner which was causative of this increase in HO-1 vicariously through activation of Nrf2.[18]

Induction of HO-1 also appears to be the mechanism underlying protection against myocardial ischemia-reperfusion from Higenamine.[19]

Higenamine appears to be protective under instances of Ischemia (lack of oxygen), with the exact mechanisms known but not yet compared to an active control (to assess potency of these protective effects)

4Cardiovascular Health


In serum isolated from rats and humans, Higenamine appears to have antiplatelet aggregating propeties with an IC50 value of 140uM in response to Arachidonic Acid (AA) induced clotting, noted to be half as effective as Aspirin (used as an active control), but against U46619-induced aggregation Higenamine (73uM IC50) was more effective than Aspirin on rat platelets[20] and show efficacy on collagen and ephinephrine-induced aggregation as well.[21] Higenamine may directly compete at TA receptors (Arachidonic acid metabolizes to Thromboxane A2 and acts on these receptors to induce platelet aggregation[22]) since it seems fairly weak at actually suppressing Arachidonic Acid metabolism into Thromboxane A(2) with an IC50 2990uM.[20] Anti-thrombotic effects have been observed in mouse acute thrombosis model and rat AV shunt models after oral ingestion of 50-100mg/kg bodyweight[23] and after oral administration of 10-50mg/kg Higenamine in a rat model of disseiminated intravascular coagulation;[24] the S-Enantiomer may be more potent than the R-enantiomer of Higenamine,[25] but the previous studies used a racemic mixture of the two.

Higenamine per se appears to have anti-thrombotic potential, which seems to be related to competing with Thromboxane A(2) at the receptor level. These have been noted at oral intakes of 50-100mg in rats (8-16mg in humans)

4.2Cardiac tissue

Higenamine can increase the rate and force of contraction of the heart with EC50 values of 38nM and 97nM respectively, with the maximal response (3uM) being comparable to isoproterenol (100nM) although on the EC50 basis it was 20-fold less potent.[26] This positive chronotropic response to Higenamine was via activation of the adrenergic B1 receptors, and submaximal concentrations of Higenamine (2.5nM) that per se do not influence contractile rate can augment Aconitate-induced contractile rate secondary to B1 agonism.[26]

A positive ionotropic effect of Higenamine also exists with an EC50 of 97nM (95% CI of 81.5-115.2nM), again being approximately 20-fold less potent than isoproterenol.[26]

Has the same mechanisms as other beta adrenergic agonists to increase heart rate; the oral dose required for this is not currently known

5Interactions with Fat Metabolism


Higenamine is known as a Beta-adrenergic receptor agonist, a mechanism shared by ephedrine and synephrine for their ability to reduce fat mass. These effects appears to be wide-reaching affecting intestinal tissue,[27] bronchiol tissue (where it acts as a vasodilator),[8] cardiac tissue (atria[26][28] and ventricles[6]). It appears to act on both the Beta(1) and Beta(2) subunit, with the Beta(3) subunit unexplored.

In regards to the alpha-adrenergic receptors, Higenamine appears to be a weak A(1) antagonist and a weak A(2) agonist.[29][8]

Possesses the same mechanisms as other stimulant fat burners to induce fat loss, but currently no evidnce exists to suggest potency of these effects in vivo

6Inflammation and Immunology


Higenamine is able to inhibit LPS-induced nitrite accumulation in macrophages, with an IC50 value of 53.4+/-2.6μM; this measurement for the racemic mixture was mostly due to S-Higenamine with an IC50 of 26.2+/-7.6μM (R-Higenamine with a value of 6, 86.3+/-5.4μM).[30] Reductions in the inflammatory response in isolated macrophages have been replicated elsewhere with similar potency to tetrandrin at the same concentration (0.01mM).[31]

A subsequent injection of 10mg/kg of the S-enantiomer reduced serum nitric oxide (induced by exposure to endotoxin) from 88+/-7μM to 28+/-5μM (68% decrease), with some efficacy from the racemic mixture and a higher dose of 20mg/kg being required for the weaker R-enantiomer.[30] These effects may be downstream of Higenamine reducing induction of iNOS (IC50 53+/-2.6μM) via NF-kB inhibition,[7] and decreases in serum nitric oxide (elevated during shock) replicated[7] and possibly secondary to NF-kB inhibition.[7]

Appears to possess anti-inflammatory mechanisms and may be useful in clinical settings for septic shock

7Interactions with Organ Systems

7.1Lungs and Asthma

Higenamine was found secondary to the fruits of Nandina domestica, which are a tradional asthmatic medication, to act on beta(2)adrenergic recpetors; the same receptor class that ephedrine and synephrine act upon.[2] The anti-asthmatic effects of Higenamine are wholly mediated via this receptor,[2][8] and activation of the beta(2)adrenergic receptor is anti-asthmatic in nature due to inducing bronchiol dilation (widening of breathing tubes). It should be noted that usage of Nandina domestica for anti-asthmatic effects may be more effective than Higenamine in isolation due to nantenine, another bioactive that has anti-asthmatic effects.[3]

When guinea pigs are exposed to histamine who were pretreated with test drugs, Higenamine was able to delay bronchiol convulsion by 1.7-fold relative to control (slightly underperforming salbuterol as active control, which exerted a 2.3-fold delay over control).[8] The benefit was dose dependent, and a higher concentration of Higenamine was more effective.

Nandina domestica has a long history of being helpful for asthmatics, and Higenamine is thought to contribute benficially. No actual interventions in living creatures exist aside from one Hamster study, suggesting similar potency to Salbuterol


In a study where low doses of Higenamine were injected into the rat penis (to avoid circulation and to better assess penile physiology), 0.0005mg/kg to 0.002mg/kg Higenamine increased relaxation of the corpus cavernosum in a dose-dependent manner with 1mM inducing 92.5+/-6.9% relaxation.[1] This relaxation was attenuated with propanolol, and thus was mediated via Beta(2)adrenergic agonsitic properties; and increased both cAMP and cGMP in a concentration dependent manner.[1]

Pre-treatment of rat corpus cavernosums with Higenamine enhanced the relaxation effects of PDE5 inhibitors, suggesting possible additive or synergistic effects.[1]

Appears to be proerectile, but no studies exist to connect the one rat study (injections) to oral dosing; may be synergistic with PDE5 inhibitors (Horny Goat Weed, Sophora Flavescens, Viagra)

8Safety and Toxicity

A study cited in this paper[11] but otherwise inaccessible, from the journal Zhongguo Lin Chuang Yao Li Xue Za Zhi (Y.R Du et al.) suggests that the highest safe/recommended dose in humans is 24mcg/kg bodyweight as higenamine hydrochloride. Rabbit studies appear to use 50mg/kg acutely with no harm acutely (correlates to 11mg/kg[32]) but no long term studies have been conducted.

Limited safety evidence on Higenamine


  1. ^ a b c d e Kam SC, et al. The relaxation effect and mechanism of action of higenamine in the rat corpus cavernosum. Int J Impot Res. (2012)
  2. ^ a b c d e f g h Tsukiyama M, et al. Beta2-adrenoceptor-mediated tracheal relaxation induced by higenamine from Nandina domestica Thunberg. Planta Med. (2009)
  3. ^ a b Ueki T, et al. Biphasic tracheal relaxation induced by higenamine and nantenine from Nandina domestica Thunberg. J Pharmacol Sci. (2011)
  4. ^ a b Kashiwada Y, et al. Anti-HIV benzylisoquinoline alkaloids and flavonoids from the leaves of Nelumbo nucifera, and structure-activity correlations with related alkaloids. Bioorg Med Chem. (2005)
  5. ^ Chang YC, et al. Cytotoxic benzophenanthridine and benzylisoquinoline alkaloids from Argemone mexicana. Z Naturforsch C. (2003)
  6. ^ a b Kimura I, et al. Inotropic effects of (+/-)-higenamine and its chemically related components, (+)-R-coclaurine and (+)-S-reticuline, contained in the traditional sino-Japanese medicines "bushi" and "shin-i" in isolated guinea pig papillary muscle. Jpn J Pharmacol. (1989)
  7. ^ a b c d e Kang YJ, et al. Inhibition of activation of nuclear factor kappaB is responsible for inhibition of inducible nitric oxide synthase expression by higenamine, an active component of aconite root. J Pharmacol Exp Ther. (1999)
  8. ^ a b c d e Bai G, et al. Identification of higenamine in Radix Aconiti Lateralis Preparata as a beta2-adrenergic receptor agonist1. Acta Pharmacol Sin. (2008)
  9. ^ Praman S, et al. Hypotensive and cardio-chronotropic constituents of Tinospora crispa and mechanisms of action on the cardiovascular system in anesthetized rats. J Ethnopharmacol. (2012)
  10. ^ Minami H, et al. Functional analysis of norcoclaurine synthase in Coptis japonica. J Biol Chem. (2007)
  11. ^ a b c Feng S, Hu P, Jiang J. Determination of higenamine in human plasma and urine using liquid chromatography coupled to positive electrospray ionization tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. (2011)
  12. ^ Feng S, et al. A phase I study on pharmacokinetics and pharmacodynamics of higenamine in healthy Chinese subjects. Acta Pharmacol Sin. (2012)
  13. ^ a b c d e f g Lo CF, Chen CM. Determination of higenamine in plasma and urine by high-performance liquid chromatography with electrochemical detection. J Chromatogr B Biomed Appl. (1994)
  14. ^ a b c d e f Pharmacokinetics of Higenamine in Rabbits.
  15. ^ a b Nojima H, Okazaki M, Kimura I. Counter effects of higenamine and coryneine, components of aconite root, on acetylcholine release from motor nerve terminal in mice. J Asian Nat Prod Res. (2000)
  16. ^ Shin JS, et al. Inhibitory effects of higenamine on dopamine content in PC12 cells. Planta Med. (1999)
  17. ^ Tabrez S, et al. A synopsis on the role of tyrosine hydroxylase in Parkinson's disease. CNS Neurol Disord Drug Targets. (2012)
  18. ^ a b c Ha YM, et al. Higenamine reduces HMGB1 during hypoxia-induced brain injury by induction of heme oxygenase-1 through PI3K/Akt/Nrf-2 signal pathways. Apoptosis. (2012)
  19. ^ Lee YS, et al. Higenamine reduces apoptotic cell death by induction of heme oxygenase-1 in rat myocardial ischemia-reperfusion injury. Apoptosis. (2006)
  20. ^ a b Pyo MK, et al. Effects of higenamine and its 1-naphthyl analogs, YS-49 and YS-51, on platelet TXA2 synthesis and aggregation. Thromb Res. (2007)
  21. ^ Yun-Choi HS, et al. Antithrombotic effects of YS-49 and YS-51--1-naphthylmethyl analogs of higenamine. Thromb Res. (2001)
  22. ^ Halushka PV. Thromboxane A(2) receptors: where have you gone. Prostaglandins Other Lipid Mediat. (2000)
  23. ^ Yun-Choi HS, et al. Anti-thrombotic effects of higenamine. Planta Med. (2001)
  24. ^ Yun-Choi HS, et al. The effects of higenamine on LPS-induced experimental disseminated intravascular coagulation (DIC) in rats. Planta Med. (2002)
  25. ^ Pyo MK, et al. Enantioselective synthesis of (R)-(+)- and (S)-(-)-higenamine and their analogues with effects on platelet aggregation and experimental animal model of disseminated intravascular coagulation. Bioorg Med Chem Lett. (2008)
  26. ^ a b c d Kimura I, et al. Positive chronotropic and inotropic effects of higenamine and its enhancing action on the aconitine-induced tachyarrhythmia in isolated murine atria. Jpn J Pharmacol. (1994)
  27. ^ Liu W, et al. Effects of higenamine on regulation of ion transport in guinea pig distal colon. Jpn J Pharmacol. (2000)
  28. ^ Park CW, Chang KC, Lim JK. Effects of higenamine on isolated heart adrenoceptor of rabbit. Arch Int Pharmacodyn Ther. (1984)
  29. ^ Liu XJ, Wagner HN Jr, Tao S. Measurement of effects of the Chinese herbal medicine higenamine on left ventricular function using a cardiac probe. Eur J Nucl Med. (1983)
  30. ^ a b Park JE, et al. Enantiomers of higenamine inhibit LPS-induced iNOS in a macrophage cell line and improve the survival of mice with experimental endotoxemia. Int Immunopharmacol. (2006)
  31. ^ Lee HY, et al. Inhibition of lipopolysaccharide-induced inducible nitric oxide (iNOS) mRNA expression and nitric oxide production by higenamine in murine peritoneal macrophages. Arch Pharm Res. (1999)
  32. ^ Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers.
  33. Dhingra D, et al. Dietary fibre in foods: a review. J Food Sci Technol. (2012)
  34. Mattes RD, Kris-Etherton PM, Foster GD. Impact of peanuts and tree nuts on body weight and healthy weight loss in adults. J Nutr. (2008)
  35. de Jonge L, Bray GA. The thermic effect of food and obesity: a critical review. Obes Res. (1997)
  36. Clegg ME and Cooper C. Exploring the myth: Does eating celery result in a negative energy balance?. Proc Nutr Soc. (2012)
  37. Rezaeipour M, Apanasenko GL, Nychyporuk VI. Investigating the effects of negative-calorie diet compared with low-calorie diet under exercise conditions on weight loss and lipid profile in overweight/obese middle-aged and older men. Turk J Med Sci. (2014)
  38. Holt SH, et al. A satiety index of common foods. Eur J Clin Nutr. (1995)