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A phase II trial of huperzine A in mild to moderate Alzheimer disease


Rafii, M. S., Walsh, S., Little, J. T., Behan, K., Reynolds, B., Ward, C., Jin, S., Thomas, R., Aisen, P. S.


Neurology, Volume: 76, No.: 16, Pages.: 1389-1394

Year of Publication



Objective: Huperzine A is a natural cholinesterase inhibitor derived from the Chinese herb Huperzia serrata that may compare favorably in symptomatic efficacy to cholinesterase inhibitors currently in use for Alzheimer disease (AD).; Methods: We assessed the safety, tolerability, and efficacy of huperzine A in mild to moderate AD in a multicenter trial in which 210 individuals were randomized to receive placebo (n = 70) or huperzine A (200 μg BID [n = 70] or 400 μg BID [n = 70]), for at least 16 weeks, with 177 subjects completing the treatment phase. The primary analysis assessed the cognitive effects of huperzine A 200 μg BID (change in Alzheimer’s Disease Assessment Scale-cognitive subscale [ADAS-Cog] at week 16 at 200 μg BID compared to placebo). Secondary analyses assessed the effect of huperzine A 400 μg BID, as well as effect on other outcomes including Mini-Mental State Examination, Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change scale, Alzheimer’s Disease Cooperative Study Activities of Daily Living scale, and Neuropsychiatric Inventory (NPI).; Results: Huperzine A 200 μg BID did not influence change in ADAS-Cog at 16 weeks. In secondary analyses, huperzine A 400 μg BID showed a 2.27-point improvement in ADAS-Cog at 11 weeks vs 0.29-point decline in the placebo group (p = 0.001), and a 1.92-point improvement vs 0.34-point improvement in the placebo arm (p = 0.07) at week 16. Changes in clinical global impression of change, NPI, and activities of daily living were not significant at either dose.; Conclusion: The primary efficacy analysis did not show cognitive benefit with huperzine A 200 μg BID.; Classification Of Evidence: This study provides Class III evidence that huperzine A 200 μg BID has no demonstrable cognitive effect in patients with mild to moderate AD.;

Bibtex Citation

@article{Rafii_2011, doi = {10.1212/wnl.0b013e318216eb7b}, url = {}, year = 2011, month = {apr}, publisher = {Ovid Technologies (Wolters Kluwer Health)}, volume = {76}, number = {16}, pages = {1389--1394}, author = {M. S. Rafii and S. Walsh and J. T. Little and K. Behan and B. Reynolds and C. Ward and S. Jin and R. Thomas and P. S. Aisen}, title = {A phase {II} trial of huperzine A in mild to moderate Alzheimer disease}, journal = {Neurology} }


a, aged, aged, 80 and over, alkaloids, alzheimer disease, analysis of variance, apolipoproteins e, double-blind method, drug therapy, female, genetics, humans, huperzine, male, mental status schedule, middle aged, neuroprotective agents, sesquiterpenes, therapeutic use, time factors, treatment outcome

Countries of Study


Types of Dementia

Alzheimer’s Disease

Types of Study

Randomised Controlled Trial

Type of Outcomes

ADLs/IADLs, Behaviour, Cognition

Type of Interventions

Pharmaceutical Interventions

Pharmaceutical Interventions

Herbal remedies, vitamins, dietary supplements