Huperzine A


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Name: Huperzine A
Synonyms: ZT-1, DEBIO 9902 , Qian ceng ta, Cerebra capsule, Pharmassure Memorall capsule
Therapy Type: Small Molecule (timeline), Supplement, Dietary (timeline)
Target Type: Cholinergic System (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Inactive)
Company: Debiopharm Group™, Neuro-Hitech, Inc.
Approved for: None


Huperzine A is an alkaloid extract derived from the Chinese club moss Huperzia serrata. Huperzine A for many years has been widely used in traditional Chinese medicine to enhance memory and to treat fever and inflammation. In the United States it is commercially available as a food supplement, but has not been approved by the FDA as a treatment for AD or other cognition disorders.

Multiple proposed mechanisms of action for huperzine A can be found in the literature. It is a selective AChE inhibitor. It also been shown to have antioxidant and neuroprotective properties counteracting glutamate-induced toxicity, possibly by interacting with  NMDA receptors (Ashani et al., 1994Ved et al., 1997Zhang et al., 2001; Gordon et al., 2001Bai et al., 2000).

Research on huperzine A originated with the Chinese Academy of Sciences. The Mayo Clinic, Jacksonville, Florida, generated a version of huperzine A that was tested at Georgetown University, Washington, D.C., and licensed to the biotechnology company Neuro-Hitech to develop an oral formulation for clinical development. Preclinical studies of this compound suggested blood-brain barrier penetration and good tolerability and the same mechanism of action as the original Chinese extract (Neuro Hi-Tech media release). Additional formulations of huperzine A exist, as well.


Between 2004 and 2007, Neuro-Hitech's oral formulation of huperzine A completed a Phase 2 clinical trial in the United States for the treatment of Alzheimer's disease. Conducted by the Alzheimer Disease Cooperative Study, this multicenter, four-month trial compared two doses of huperzine to placebo in 210 people with mild to moderate AD. This trial was negative on its primary endpoint, but secondary analyses indicated a trend toward cognitive improvement on the higher dose (Rafii et al., 2011). Side effects, mostly nausea and vomiting, were mild to moderate. Development of this formulation has been discontinued.

A second trial, of a sustained-release formulation developed by Shandong Luye Pharmaceutical Co., Ltd., began in 2010 and was estimated to run for two years. According to, this Phase 2/3 study was conducted at the Shanghai Mental Health Center, to compare a six-month course of two doses to placebo in 390 people with mild to moderate Alzheimer's disease. The status of this trial is unknown and data are unavailable.

The Swiss company Debiopharm tested a synthetic huperzine derivative and prodrug, ZT-1, aka DEBIO 9902. It was reported to be well-tolerated, rapidly absorbed, and converted into huperzine A, in a small Phase 1 trial in healthy Chinese volunteers ( Jia et al., 2013). However, clinical development of DEBIO 9902 has been discontinued.

Previously, clinical trials conducted in China had reported beneficial effects on cognition. These were two-week to two-month trials in 60, 103, and 160 patients with dementia, respectively (see Xu et al., 1999; Xu et al., 1995). 

A published meta-analysis of 20 huperzine clinical trials conducted in China, Europe, and the United States leaves open the question of whether huperzine could be therapeutically useful. Trials reporting beneficial effects have tended to be small and of short duration (Yang et al., 2013). A separate attempt to evaluate clinical trials of huperzine A for mild cognitive impairment found no studies that met inclusion criteria for meta-analysis, that is, randomised, parallel-group, placebo-controlled trials (Yue et al., 2012). Research on huperzine A continues.

Last Updated: 30 Oct 2012


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Paper Citations

  1. . A phase II trial of huperzine A in mild to moderate Alzheimer disease. Neurology. 2011 Apr 19;76(16):1389-94. PubMed.
  2. . Phase I study on the pharmacokinetics and tolerance of ZT-1, a prodrug of huperzine A, for the treatment of Alzheimer's disease. Acta Pharmacol Sin. 2013 Jul 5;34(7):976-82. PubMed.
  3. . Huperzine-A in capsules and tablets for treating patients with Alzheimer disease. Zhongguo Yao Li Xue Bao. 1999 Jun;20(6):486-90. PubMed.
  4. . Efficacy of tablet huperzine-A on memory, cognition, and behavior in Alzheimer's disease. Zhongguo Yao Li Xue Bao. 1995 Sep;16(5):391-5. PubMed.
  5. . Huperzine a for Alzheimer's disease: a systematic review and meta-analysis of randomized clinical trials. PLoS One. 2013;8(9):e74916. Epub 2013 Sep 23 PubMed.
  6. . Huperzine A for mild cognitive impairment. Cochrane Database Syst Rev. 2012;12:CD008827. PubMed.
  7. . Role of tyrosine 337 in the binding of huperzine A to the active site of human acetylcholinesterase. Mol Pharmacol. 1994 Mar;45(3):555-60. PubMed.
  8. . Huperzine A, a potential therapeutic agent for dementia, reduces neuronal cell death caused by glutamate. Neuroreport. 1997 Mar 3;8(4):963-8. PubMed.
  9. . Huperzine A, a nootropic alkaloid, inhibits N-methyl-D-aspartate-induced current in rat dissociated hippocampal neurons. Neuroscience. 2001;105(3):663-9. PubMed.
  10. . The NMDA receptor ion channel: a site for binding of Huperzine A. J Appl Toxicol. 2001 Dec;21 Suppl 1:S47-51. PubMed.
  11. . Huperzine A, a potential therapeutic agent for treatment of Alzheimer's disease. Curr Med Chem. 2000 Mar;7(3):355-74. PubMed.

External Citations

  1. Neuro Hi-Tech media release

Further Reading


  1. . New nicotinic analogue ZY-1 enhances cognitive functions in a transgenic mice model of Alzheimer's disease. Neurosci Lett. 2013 Mar 14;537:29-34. PubMed.
  2. . Huperzine a restores cortico-hippocampal functional connectivity after bilateral AMPA lesion of the nucleus basalis of meynert. J Alzheimers Dis. 2013 Jan 1;35(4):833-46. PubMed.
  3. . The effects of huperzine A on gastrointestinal acetylcholinesterase activity and motility after single and multiple dosing in mice. Exp Ther Med. 2013 Mar;5(3):793-796. PubMed.
  4. . Simultaneous determination of ZT-1 and its metabolite Huperzine A in plasma by high-performance liquid chromatography with ultraviolet detection. J Chromatogr B Analyt Technol Biomed Life Sci. 2006 Jan 2;830(1):120-5. Epub 2005 Nov 8 PubMed.