Understanding Huperzine A

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Understanding Huperzine A

By Shota Yamamoto, M.D.

Fig: Taken from https://www.nature.com/nsmb/journal/v4/n1/abs/nsb0197-57.html - Raves et al. Structure of acetylcholinesterase complexed with the nootropic alkaloid, (−)-huperzine A. Nature Structural Biology. 1997.

This is a summary of the article The psychopharmacology of huperzine A: an alkaloid with cognitive enhancing and neuroprotective properties of interest in the treatment of Alzheimer's disease – Zangara. Pharmacology Biochemistry and Behavior. 2003.

Huperzine A (HupA) is a plant-based alkaloid that has been used for centuries to treat fever, inflammation, blood disorders and schizophrenia (1). This substance is found in the Chinese club moss known as H. serrata and acts as a potent reversible inhibitor of acetylcholinesterase (AChE) that crosses the blood–brain barrier to enter into the brain. Cholinesterase inhibitors, which inhibit acetylcholine (ACh) subsequently increases the amount of acetylcholine (ACh) at the neuronal synaptic cleft by inhibiting the enzyme responsible for the hydrolysis of ACh and consequently improve neuronal transmission.

HupA has been found to reverse or attenuate cognitive deficits in several animal models, water maze (2), delayed response performance (3), and cognition enhancement in aged monkeys in a delayed recognition task (4). Clinical trials in China, where it has been approved and clinically used as a symptomatic agent for Alzheimer’s disease (AD), demonstrated a significant improvement in memory.

In the United States, where HupA is not yet approved by the FDA, it is sold as a dietary supplement for memory loss and mental impairment. It has rapidly become a cult supplement in the smart-drugs market and a hot selling item.

HupA may also reduce neuronal cell death caused by an excess of glutamate (5), an action that further enhances the potential value of HupA as a therapeutic agent for AD. It is also a powerful neuroprotective and antioxidant agent (6) and a protective against amyloid beta peptide-induced neuronal cell death (apoptosis) (7).

A reduction in the level of abnormal free radicals was demonstrated in a study on the effects of HupA on lipid peroxidation and superoxide dismutase in the hippocampus, cerebral cortex and serum of aged rats (8). A reduction in the plasma and erythrocyte oxygen free radicals was also demonstrated in a clinical study (9).

A randomized, double blind study in 2002 (10) evaluated the use of HupA in patients meeting the DSM IV criteria for possible or probable AD. Two-hundred and two patients aged between 50 and 80 years were enrolled from 15 centers in five cities in China. Patients were randomly divided into a HupA treatment group (n=100) and a placebo group (n=102). The results were assessed using ability of daily life (ADL), ADAS-Cog, ADAS-non-Cog, MMSE, and CIBIC-plus scales. The results indicated that HupA improved cognitive function and indices of daily life and behavior. This results were confirmed by the care givers who reported a significant improvement of the patients in daily life.

Finally, the efficacy of HupA has also been tested in young adults. The effect of HupA on the performance of junior middle school students was studied using a double-blind, matched-pair design for 4 weeks (11) in Junior middle school students (n=68) who were complaining of learning and memory problems were divided into two paired groups according to normal psychological health inventory, similar memory quotient, same gender and class. At the beginning and end of the trial, the students were evaluated with the WMS and the TESS, and they performed tests of English, Chinese and mathematics. The findings of this study were that HupA improved memory. There were significant differences on MQ in both groups where the MQ of the HupA group was also significantly higher (P<.01) at the end of the 4 weeks, than that of the placebo group.

Cut to the chase/Thoughts:

To summarize, HupA inhibits AChE that allows the brain to increase the level of ACh, which is one of the treatments for AD. Not only does HupA help with patients who have AD, but it seems to also help with younger patients who have no systemic disease. As a bonus, there is a correlation between HupA and neuroprotection, as well as decrease in free radical levels.


    1. J.S. Liu, Y.L. Zhu, C.M. Yu, et al. The structure of huperzine A and B, two new alkaloids exhibiting marked anticholinesterase activity. Can. J. Chem., 64 (1986), pp. 837-839
    2. J. Liu, H.Y. Zhang, X.C. Tang, B. Wang, X.C. He, D.L. Bai. Effects of synthetic (−)-huperzine A on cholinesterase activities and mouse water maze performance. Acta Pharmacol. Sin., 19 (1998), pp. 413-416
    3. X.C. Tang, Y.F. Han, X.P. Chen, X.D. Zhu. Effects of huperzine A on learning and retrieval process of discrimination performance in rats. Acta Pharmacol. Sin., 7 (1986), pp. 501-511
    4. J.W. Ye, J.X. Cai, L.M. Wang, X.C. Tang. Improving effects of huperzine A on spatial working memory in aged monkeys and young adult monkeys with experimental cognitive impairment. J. Pharmacol. Exp. Ther., 288 (1999), pp. 814-819
    5. H.S. Ved, M.L. Koenig, J.R. Dave, B.P.Doctor. Huperzine A, a potential therapeutic agent for dementia, reduces neuronal cell death caused by glutamate. Neuroreport, 8 (1997), pp. 963-968
    6. X.Q. Xiao, R. Wang, X.C. Tang. Huperzine A and tacrine attenuate beta-amyloid peptide-induced oxidative injury. J. Neurosci. Res., 61 (2000), pp. 564-569
    7. Y.Z. Shang, J.W. Ye, X.C. Tang. Improving effects of huperzine A on abnormal lipid peroxidation and superoxide dismutase in aged rats. Acta Pharmacol. Sin., 20 (9) (1999), pp. 824-828
    8. X.Q. Xiao, R. Wang, X.C. Tang. Huperzine A and tacrine attenuate beta-amyloid peptide-induced oxidative injury. J. Neurosci. Res., 61 (2000), pp. 564-569
    9. S.S. Xu, Z.Y. Cai, Z.W. Qu, R.M. Yang, Y.L. Cai, G.Q. WangHuperzine-A in capsules and tablets for treating patients with Alzheimer's disease. Acta Pharmacol. Sin., 20 (1999), pp. 486-490
    10. H.Y. Zhang, Y.Q. Liang, X.C. Tang, X.C.He, D.L. Bai. Stereoselectivities of enantiomers of huperzine A in protection against beta-amyloid (25–35)-induced injury in PC12 and NG108-15 cells and cholinesterase inhibition in mice. Neurosci. Lett., 317 (3) (2002), pp. 143-146
    11. Q.Q. Sun, S.S. Xu, J.L. Pan, H.M. Guo, W.Q. Cao. Efficacy of huperzine A capsules on memory and learning performance in 34 pairs of matched junior middle school students. Acta Pharmacol. Sin., 20 (1999), pp. 601-603

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