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I see that LifeLink’s huperzine-A product has been reformulated and renamed ‘Knoitol’

Q:I see that LifeLink’s huperzine-A product has been reformulated and renamed ‘Knoitol’ (how cute: ‘Know-it-all’). For years I have occasionally used LifeLink’s original huperzine supplement as a cognitive enhancer. It seemed to be somewhat helpful for my memory (though not dramatically so). The new dosage is four times as high as the old one. Why the change? Is it known to be more effective at this higher dosage?

A:LifeLink’s original formulation (50 mcg huperzine-A per capsule) was based on what was widely known in the 1990s — that the average person can see modest improvements in memory function at that dosage. What was not widely known at that time was that in China researchers were running clinical trials using huperzine-A to treat Alzheimer’s disease. The results of these studies were mostly ignored outside of China until recently. However, it is now clear that higher dosages (up to 800 mcg/day) significantly ameliorate the symptoms of Alzheimer’s Disease. Furthermore, the Chinese have shown that higher doses of huperzine show better cognitive enhancement in people who don’t have Alzheimer’s.


Huperzine-A (HupA), a substance found in the club moss Huperzia serrata, has been used in China for centuries to treat swelling, fever, and blood disorders.1 Because it is a plant-derived substance with a history of traditional use, it is available in the U.S. as a nutritional supplement.

In China the Chinese Academy of Sciences took an interest in HupA in the 1980s and developed it as a treatment for dementia, particularly the dementia of Alzheimer’s Disease. It is now the approved treatment for Alzheimer’s in China.3

In most respects HupA appears to be superior to all anti-Alzheimer’s drugs currently approved by the U.S. Food and Drug Administration — drugs such as tacrine, donepezil, and rivastigmine. HupA has better penetration through the blood-brain barrier, higher oral bioavailability, fewer side effects, and a longer duration of action than these expensive prescription drugs.2,3

The medical studies

Nearly all medical research on huperzine is the work of researchers in China who conducted animal studies and human clinical trials. During the 1980s, 1990s, and early 2000s, they reported that HupA enhances memory and protects nerve cells from the kinds of damage typically seen in Alzheimer’s Disease. Double-blind, placebo-controlled clinical trials in patients with and without Alzheimer’s resulted in significant improvements in cognitive function and in the quality of life.1,4,5,6,7,8 But these results had little impact in the medical world outside China. Finally, in 2004 the U.S. National Institutes of Health (in collaboration with a company that hopes to turn HupA into a prescription drug19) organized a clinical trial to study HupA in Alzheimer’s patients. The trial was completed in 2006, but the results have not yet been published.9 Other clinical trials are being planned.19

Animal studies have shown that HupA protects the nervous system from organophosphate nerve-gas agents.2,10 This fact has no relevance to supplement buyers except insofar as it provides further evidence of huperzine’s powerful neuroprotective action.

How does huperzine work?

HupA appears to affect multiple biochemical pathways in the brain, several of which are involved in Alzheimer’s Disease. The best understood of these pathways is the one in which the neurotransmitter acetylcholine carries signals from one nerve cell to another in certain parts of the brain. In Alzheimer’s Disease, there is a shortage of acetylcholine, and consequently an impaired signalling ability. HupA is an inhibitor of the enzyme that breaks down acetylcholine. Thus, HupA causes this neurotransmitter to accumulate in the space between the cells, permitting higher levels of signalling to take place.

If this were huperzine’s only effect on Alzheimer’s, it would have no advantage (other than price) over the prescription drugs currently available — i.e., it would merely compensate temporarily for the impairment caused by damaged and dead nerve cells, but it would not slow the destruction of nerve cells or bring about the repair of damaged tissue. But as luck would have it, HupA has additional modes of action:11,12,13,14,2,6,15

  • It protects nerve cells from free radicals generated by the ‘beta-amyloid’ protein plaques found in Alzheimer’s brain tissue.
  • It interferes with the formation of these destructive beta-amyloid plaques.
  • It interferes with the ‘suicide’ programming that causes nerve cells to die when they receive spurious ‘time-to-die’ signals, as they do under Alzheimer’s conditions.
  • It increases the brain’s production of nerve growth factor (NGF) — a substance involved in generating replacements for lost cells.
  • It increases the brain’s production of NGF receptors — cell-surface proteins that are required for NGF activity.

Dosage used in Alzheimer’s studies

Until recently, supplement companies sold huperzine as a cognitive enhancer for people whose cognitive abilities fell into the normal range, and the dosages were small — 50 mcg/day, for example. But now that the Chinese studies on Alzheimer’s patients have become known outside of China, it is realized that larger doses are needed. The latest clinical studies use 400–800 mcg/day.9LifeLink has therefore increased the dosage in its HupA product Knoitol to 200 mcg per capsule.

Does huperzine repair stroke damage?

Although the final word has not been heard on this subject, preliminary experiments with gerbils and other animals indicate that HupA limits memory deficits and neuronal damage after stroke-like brain injuries.16,17 Gerbils with such injuries were given HupA orally at 0.1 mg/kg twice per day for 14 days. (This is a much larger relative dose than is used in human Alzheimer’s studies.)


As mentioned above, one clinical trial of huperzine-A for treating Alzheimer’s Disease has been conducted in the United States. Others are planned, including one to treat Myasthenia Gravis, a chronic autoimmune neuromuscular disorder. The co-sponsor of these trials is Neuro-Hitech, Inc., a company that hopes to turn huperzine into a prescription drug.19 Upon completion of the Alzheimer’s clinical trials, we can expect that Neuro-Hitech will petition the U.S. FDA to ban huperzine as a supplement and redefine it to be a prescription drug. The Dietary Supplement Health and Education Act of 1994 prohibits the FDA from doing this because huperzine is a plant-derived substance with a history of traditional use and is therefore classified as a supplement. I predict, however, that the FDA will disregard the law and go along with Neuro-Hitech’s scheme unless it is stopped by lawsuits or public outcry. If huperzine-A does become a prescription drug and is banned as a supplement, its price in the U.S. and similar countries will become exhorbitant and Neuro-Hitech, Inc., will become very rich — merely as the result of copying clinical studies done in China more than a decade ago.

For further reading

I recommend the following review articles for readers who want to start exploring the medical literature on the subject of huperzine as a treatment for Alzheimer’s: Akhondzadeh20, Doraiswamy18, Jiang3, and Zhang11.


Disclaimer: The information provided in this “Ask Dr. Zarkov” article contains no medical advice whatsoever — it contains biological information. Nothing in the article constitutes an effort to persuade readers to use, or not to use, this biological information as a basis for action.

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