Huperzine A: An Underappreciated Solution to the Aging Brain
Sometimes the popularity of a natural product is based more on great marketing rather than scientific merit. And, sometimes, very effective and scientifically validated natural products never achieve any real commercial success. One of the best examples of this latter situation is Huperzine A – a naturally occurring alkaloid compound found in Chinese club moss (Huperzia serrata). Have you heard of it? And, if you have, do you know how valuable this natural product can be for those in need of its health benefits?

Huperzine A (Hup A) exerts a multitude of beneficial actions on the brain, but foremost is its ability to inhibit the breakdown of the neurotransmitter acetylcholine (ACH) – a key brain chemical for memory. A deficiency of action of ACH is one of the hallmark features of Alzheimer’s disease (AD) as well as poor memory and concentration. By preventing the breakdown of ACH, Hup A can enhance its action and produce clinically meaningful effects in AD and poor memory and cognition. In fact, it may have the best documented effects in these application of any natural product.

Background Data:

The earliest record of medicinal usage of Huperzia serrata can be traced back to an ancient Chinese pharmacopeia “Ben CaoShi Yi” written in 739 AD. The modern investigation of Huperzia and Lycopodium alkaloids began in the early 1980s, Chinese scientists were searching for new drugs for the treatment of myasthenia gravis – a long-term neuromuscular disease caused by an autoimmune attack receptors for the neurotransmitter acetylcholine. Researchers were looking for new inhibitors of the enzyme acetylcholinesterase (AChE). This enzyme breaks down acetylcholine. By inhibiting AChE, there is a potentiation of the acetylcholine effect leading to some improvement in myasthenia gravis. The end point of the investigation into new AChE inhibitors was the discovery of Hup A as the most potent of these compounds.

Huperzine A Summary

Huperzine A is a natural cholinesterase inhibitor extracted, isolated and purified from the indigenous Chinese herb, Huperzia serrata

The activity (mechanism(s) of action) profile of Huperzine A compares favorably to prescription cholinesterase inhibitors, and offer multiple advantages

The tolerability profile of Huperzine A is more favorable than prescription cholinesterase inhibitors, and offers multiple advantages

Studies indicate that Huperzine A provides neuroprotective/antioxidant properties, in addition to cholinesterase inhibition

Crude preparations of Huperzia serrata contain compounds that counteract Huperzine A and do not offer the same degree of efficacy and safety as pure Huperzine A.

A Quick Look at Hup A and Acetylcholine Function

Acetylcholine is a brain chemical that plays a central role in memory, especially the encoding of new memories. Acetylcholine is especially important in certain key areas of the brain that are damaged during the development of AD (e.g., entorhinal cortex and hippocampus). Not surprisingly, drugs that are acetylcholinesterase inhibitors (AChEIs) have emerged as the dominant treatment target in AD. Unfortunately, the currently available drugs that are AChEIs have shortcomings including poor tolerability and lack of action on key brain AChE receptors. These drugs include donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne). Tacrine (Cognex), the first AchE inhibitor approved for AD was also on this list, but lack of effect and poor tolerability led to its removal from the market. Side effects included nausea, vomiting, dizziness, diarrhea, seizures, and syncope. Also, four times a day dosing regimen was required, and patients required periodic blood monitoring due to liver toxicity.

How Hup A is Different

If these drugs have shown limited effects and poor tolerability in AD, how is Hup A different? First, Hup A is a highly selective, reversible, and potent AchE inhibitor. Hup A is 8- and 2-fold more potent than drug ACEIs in increasing cortical acetylcholine levels, with a longer-lasting effect. Hup A also has a higher oral bioavailability compared to conventional drug AChEIs. It is also able to cross the blood-brain-barrier more efficiently. Furthermore, Hup A exerts much different effects via acting preferentially within the synapse connecting brain cells and also acts preferentially on specific forms of AchE that is concentrated within the areas of the brain most affect in AD, i.e., the hippocampus and frontal cortex are most abundant in these forms of AchE.


Hup A exerts a number of other actions that are important to its overall beneficial effects including:

  • Dampening effect of β-amyloid toxicity
  • Prevention of brain cell damage by neurotoxins
  • Direct antioxidant activity
  • Enhancing the activities of endogenous antioxidant enzymes such as glutathione peroxidase, catalase, and superoxide dismutase
  • Increases nerve growth factor production
  • Promotes brain cell recovery.

Clinical Effects in Alzheimer’s Disease

Here is something to consider: Hup A is the drug of choice in China for the treatment of AD and memory disorders and has been for many years. Hup A has been a prescription drug in China since the early 1990s and has reportedly been used with no serious adverse effects. In addition to the considerable clinical data produced from studies conducted in China, phase II clinical trials have been conducted with Hup A in AD in over 30 sites in the US and Europe. A detailed meta-analysis of 20 randomized clinical trials with 1823 participants concluded that “Huperzine A appears to have beneficial effects on improvement of cognitive function, daily living activity, and global clinical assessment in participants with Alzheimer’s disease.” Compared with placebo, Hup A showed a significant beneficial effect on the improvement of cognitive function as measured by Mini-Mental State Examination (MMSE) at 8 weeks, 12 weeks and 16 weeks, and by Hastgawa Dementia Scale (HDS) and Wechsler Memory Scale (WMS) at 8 weeks and 12 weeks. Activities of daily living favored Huperzine A as measured by Activities of Daily Living Scale (ADL) at 6 weeks, 12 weeks and 16 weeks. Hup A was well tolerated in all of these trials.


The dosage used in these trials was typically 200 mcg twice daily. However, this dosage level may not be sufficient in AD. For example, a trial using a lower dose of 200 mcg twice daily showed no improvement on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) scores, but a different trial using a higher dose of 400 mcg twice daily showed statistically significant improvement in the ADAS-cog scores compared to placebo. Therefore, it appears that in AD, a dosage of 400 mcg twice daily is required. This dosage does carry with it a higher rate of minor gastrointestinal side effects (nausea, vomiting and diarrhea) in about 10-20% of users.


This dose comparison trial provides many insights. The study was conducted at the School of Medicine, University of California, San Diego, and the School of Medicine, Georgetown University, Washington, DC. The objective of the study was to assess the safety, tolerability, and efficacy of Hup A in mild to moderate AD in a multicenter trial in which 210 individuals were randomized to receive placebo or Hup A (200 mcg twice daily or 400 mcg twice daily), for at least 16 weeks. The primary analysis assessed the cognitive effects of treatment with the ADAS-Cog at week 16. While Hup A at the dosage of 200 mcg twice daily did not influence change in ADAS-Cog at 16 weeks, Hup A at a dosage of 400 mcg twice daily showed a 1.92-point improvement vs. 0.34-point improvement in the placebo arm at week 16. The ADAS-Cog was developed as an outcome measure for dementia interventions. It assesses multiple cognitive domains including memory, language, praxis, and orientation. Overall, the ADAS-Cog provides excellent validation of clinical effects of an intervention in AD. In general, a 1.92-point improvement signifies quite a positive effect on global mental function by Hup A at the dosage of 400 mcg twice daily. Hup A was well-tolerated in most subjects, but about 16% experienced some mild nausea as the primary side effect.

Hup A has also been shown to be helpful in mild to moderate dementia due to reduced blood flow to the brain (vascular dementia). In a double-blind study, 78 participants were randomized to receive either vitamin C (100 mg twice daily) as the placebo or Hup A (100 mcg twice daily) for 12 consecutive weeks. The mini-mental state examination (MMSE), clinical dementia rating (CDR), and activities of daily living (ADL) scores were used for the assessment of cognition. The assessments were made prior to treatment, and 4, 8, and 12 weeks of the treatment. The adverse effects of the treatment were also recorded. After 12 weeks of treatment, the MMSE, CDR, and ADL scores significantly improved in the Hup A group, whereas the placebo group did not show any such improvement (P > 0.05 for all comparisons). No serious adverse events were recorded during the treatment. Researchers concluded Hup A “can significantly improve the cognitive function in patients with mild to moderate vascular dementia. Further, the medicament is safe.”

Nootropics are substances that may improve cognitive function, particularly executive functions, memory, creativity, or motivation, in healthy individuals. The nootropic effects of Hup A are quite promising from preliminary studies. For example, in one study, 34 pairs of matched middle school students were given Hup A (100 mcg, twice daily) or a placebo orally for 4 weeks. The memory quotient from the Wechsler Memory Scale results showed an increase from 92 to 115, as compared to the placebo group, that demonstrated an increase from 94  to 104. The performance of students in the Hup A treated group as determined by Chinese-language lesson quizzes was also higher compared with the placebo group.

Hup A has also been shown to produce improvements in cognitive function in people with major depressive disorder in preliminary studies.

Safety and Important Product Selection Guidelines

Hup A has demonstrated an excellent safety profile in all clinical trials. Although theoretical concerns over using Hup A with other cholinergic drugs seems reasonable, based upon some studies where Hup A was combined with AChE inhibitors there does not seem to be a significant risk of drug interaction.


There are a few important distinctions that must be made when selecting a Hup A product. First, all of the clinical research and safety studies with Hup A have been performed using the purified compound. This compound is substantially different from crude Huperzia serrata extracts, whether standardized or not for Hup A. The isolated Hup A is a pure compound, clinically shown to be the dietary supplement gold-standard for improvement of memory and cognition. In contrast, when it comes to crude Huperzia serrata extracts, there is no research and the composition of these extracts contains compounds with strong sedative and anti-cholinergic properties that exert effects on memory and cognition that are opposite to Hup A. In 1998, the head of the Drug Discovery Program at Georgetown University Medical Center published the following statement: “… the use of the product [Huperzia serrata] in its crude form can be extremely harmful and dangerous due to the existence of compounds other than Huperzine-A that are present in [crude form] Huperzia serrata.”


The bottom line is obvious. It is not just that cheap, low-grade crude form extracts are being promoted on the extensive favorable research – both efficacy and safety – of the purified compound, Hup A. These crude preparations carry with them the risk of significant toxicity.


Purified Hup A is the form that represents the first successful United States FDA approval as a New Dietary Ingredient (NDI). This approval signifies its enormous body of safety. It is only the purified Hup A that has been the subject of positive research conducted at these organizations:

  • National Institutes of Health
  • National Institutes on Aging
  • Alzheimer’s Disease Cooperative Study
  • Georgetown University
  • Mayo Clinic
  • The US Military, Walter Reed
  • The Chinese Military
  • Chinese Academy of Sciences
  • Shanghai Institute of Materia Medica


Again, the bottom line should be obvious. The only source of Hup A proven to be safe and effective is purified Hup A. Use of crude preparations, even if standardized for Hup A, should be avoided.

Key References:

Damar U, Gersner R, Johnstone JT, Schachter S, Rotenberg A. Huperzine A: A promising anticonvulsant, disease modifying, and memory enhancing treatment option in Alzheimer’s disease. Med Hypotheses. 2017 Feb;99:57-62.

Gul A, Bakht J, Mehmood F. Huperzine-A response to cognitive impairment and task switching deficits in patients with Alzheimer’s disease. J Chin Med Assoc. 2018; S1726-4901(18)30226-0.

Huang P, Li B, Guo YH, et al. Efficacy and safety of huperzine A in treating patients with mild cognitive impairment: a systematic review and Meta-analysis. Zhongguo Zhong Yao Za Zhi. 2019 Feb;44(3):582-588.

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