Huperzine A Influences
and Improves Personality

By Will Block

The psychologically depressed are often extremely sensitive to acetylcholine, a generalized bodily neurotransmitter that is also associated with cognition and memory functions in the brain. (In our bodies, acetylcholine is made from the choline we consume in our diet or through supplementation.) Researchers have hypothesized that deprivation of acetylcholine can increase depression. Yet experiments that reduce cholinergic activity (nerve impulses mediated by acetylcholine) have not been found to decrease the effects of antidepressants. Anticholinergics do not seem to affect antidepressants, positively or negatively.

In an attempt to explain this paradox, researchers at the University of Würzburg in Germany recently found that it takes two neurotransmitters to help tame depression. According to their findings, psychological depression is characterized by an imbalance between noradrenaline (a primary neurotransmitter of the adrenergic or catecholamine neurotransmission system) and acetylcholine (the primary neurotransmitter of the cholinergic system).

Although deprivation of acetylcholine (ACh) does not result in depression, it is often associated with irritability, brittle temperament, and, paradoxically, habitually passive strategies in stress coping. Indeed, it appears that the absence of sufficient ACh "shaves" off an important dimension of personality. It could be said that ACh is at the cutting edge of who we are, what we make of ourselves, and who we ultimately become - in more ways than one, as we shall see.

Biopsy and postmortem studies have shown that there is a substantial absence of presynaptic cholinergic neurons in Alzheimer's disease (AD) patients - they don't make enough ACh to start off with, and quickly lose much of what they do produce at the postsynaptic level, after the ACh molecules cross the synapse, where they are broken down by the enzyme acetylcholinesterase (AChE).

As chief of the cholinergic molecular cleanup crew, AChE, a protein (all enzymes are proteins), catalyzes the breakup of the acetylcholine molecule into acetate and choline. In the nervous system, nerve impulses travel from cell to cell by means of chemical messengers. What happens when an electrical impulse reaches the end of a neuron is truly amazing: messenger molecules such as ACh are released into the fluid-filled region between that neuron and its neighbor from the next cell, and they diffuse though this intercellular, synaptic gap. When they reach the destination neuron, the molecules "click" into place - like a key in a lock - at special molecular receptors, which respond by triggering new electrical impulses to transmit the signal through that cell.

Returning to AD patients, who suffer a decline in the production of ACh, the breakdown enzyme, AChE, is largely preserved in their aging brains,2 and thus its activity makes things even worse. The result is memory loss, other cognitive defects, and personality disruptions. Advanced AD patients become devoid of personality.

As we are learning, the quantity of ACh in our brain is not the whole story. It's also how efficiently we use ACh, and that involves how long we hold onto it. AChE is but one of nature's "housekeeping tools," enzymes that help to figuratively mop up or vacuum-clean various neurotransmitters, such as ACh. But the process gets out of hand or creates a larger imbalance as we age, for reasons that probably have to do with the notion that most systems evolved to operate efficiently and cooperatively only until procreation took place. After this, there was no longer an imperative that all bodily systems remain viable, and they ran down (and run down) at unequal rates.

Neurotransmitters play vital roles in the physiology of the brain and nervous system. As we age, however, the "housekeeper" enzymes become sloppy and indiscriminate. Intact molecules are vacuumed up with expended or damaged ones. The good ones, still useable, end up in the garbage heap along with the bad.

Acetylcholinesterase continually sweeps up acetylcholine molecules and splits them in two, thereby enabling the cycle of acetylcholine production to begin again. Drugs that inhibit the action of AChE are called acetylcholinesterase inhibitors and are used in the treatment of diseases of the eye (glaucoma), muscles (myasthenia gravis), and brain (Alzheimer's disease), among others. Drugs such as physostigmine, tacrine, and donepezil have also been employed for these ends, even though their mechanisms of action are not completely clear.

Recent structural analysis of the very large, convoluted AChE molecule places the active catalytic site - the specific site on that molecule at which the ACh molecule must reside for an instant before it can be split in half - deep within a gorgelike fold of the enzyme.3 (See Figure 1.) Such a configuration suggests an electrostatic mechanism drawing the positively charged ACh into the gorge and toward the active site - the "cutting edge." (See Figure 2.) It is as if the enzyme placed its victim on a sawmill table and propelled it inexorably toward the blade of destruction, which cuts it in two.

Figure 1. "Zoom-in" view of the interior of the acetylcholinesterase molecule, showing the active site at which the acetylcholine molecule (the "stick" structure) is chemically cleaved into acetate and choline.

Figure 2. Click on this image for a whimsical animated representation of AChE "cutting" ACh into choline and acetate. In reality, the ACh molecule is cleaved by a chemical reaction at the active site within the AChE molecule. There is no actual "blade."

For centuries, a traditional Chinese remedy called chien tseng ta, prepared from the plant Huperzia serrata, has been used to treat fever and inflammation. One of its constituent chemical compounds is the alkaloid huperzine A (HupA), which can be isolated from the plant or synthesized in the laboratory. Although it lacks much activity against fever and inflammation, HupA is a potent AChE inhibitor, but it has none of the negative characteristics of the drugs mentioned above.

By preferentially "hogging" the AChE molecule's active site, HupA effectively deactivates it and prevents the breakdown of ACh, thus making possible greater memory preservation, restoration, and enhancement. HupA works by jamming the cutting machinery of the AChE enzyme.

Moreover, HupA performs its tasks without significant side effects. It does not produce nasty metabolites, as do tacrine (the leading Alzheimer's drug) and other AChE inhibitors that have been approved for the treatment of AD.

Tacrine is associated with substantial liver toxicity, and in one study, these negative side effects were observed in 49% of the subjects.4 Significant adverse effects are common to all AChE inhibitors except for the phytonutrient HupA. For some AChE inhibitors, such as rivastigmine, the adverse effects include nausea, vomiting, dizziness, diarrhea, and abdominal pain.

"HupA appears to bind more tightly and specifically to acetylcholinesterase than the other AChE inhibitors," said Professor J.L. Sussman, whose team discovered the structure and the mechanism of AChE. "It is as if this natural substance were ingeniously designed to fit into the exact spot in acetylcholinesterase where it will do the most good." As well, HupA has a longer half-life - it stays active longer - than the drugs, and the molecular complex it forms with AChE has a slower rate of dissociation, which may make it a more effective therapeutic agent.

Under circumstances of neuronal emergency, such as stroke or epilepsy, glutamate release can initiate a cascade of events that can kill cells. Research has shown, however, that HupA can reduce neuronal injury and death caused by toxic levels of glutamate.5

Scientists at the Israel Institute for Biological Research, Ness-Ziona, Israel, have also found that HupA acts as a prophylactic drug against nerve-gas poisons.6 Owing to its long-lasting effects and low toxicity, HupA is finding a battlefield role in protecting against chemical weapons. It may do the same for you in the battlefield of life: the aging process.

In a recent double-blind, placebo-controlled study in China, HupA (100 mcg/day) was found to increase memory and learning performance in junior middle school students (teenagers).7 Their memory quotients were measured before and after the trial, and their academic performance in their Chinese, English, and mathematics lessons was monitored as well.

The students performed well on the accumulation, recognition, and reproduction of information, as well as association, tactile memory, and how many recitations it took them to learn something. They did significantly better in their Chinese and English lessons, but not in math. No side effects of any kind were noted.

If a full-fledged intelligence-quotient (IQ) test had been given and the results had come in as they did for the memory-quotient (MQ) test used, there would be much excitement. The students taking HupA scored significantly better (115, from a baseline of 92) than the controls (104, from a baseline of 94) on a standard MQ test that is not as well known as the Stanford-Binet IQ test. The Stanford-Binet Intelligence Scale encompasses scores in each of four domains: verbal reasoning, abstract/visual reasoning, and quantitative and short-term memory.8 Thus, to whatever degree memory improvement is reflective of overall intelligence, taking HupA could raise the chances of fulfillment and active engagement in appreciating the complexities of the world in which we live. Can we place a price on this type of pleasure? Huperzine is cheap by even the most humble evaluation of this advantage.


  1. Fritze J, Lanczik M, Sofic E, Struck M, Riederer P. Cholinergic neurotransmission seems not to be involved in depression but possibly in personality. J Psychiatry Neurosci 1995 Jan;20(1):39-48.
  2. Shinotoh H. PET study of cholinergic system in the brain. Rinsho Shinkeigaku 1999 Jan;39(1):33-5.
  3. Harel M, Schalk I, Ehret-Sabatier L, Bouet F, Goeldner M, Hirth C, Axelsen PH, Silman I, Sussman JL. Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. Proc Natl Acad Sci USA 1993 Oct 1;90(19):9031-5.
  4. Nordberg A, Svensson AL. Cholinesterase inhibitors in the treatment of Alzheimer's disease: a comparison of tolerability and pharmacology. Drug Saf 1998 Dec;19(6):465-80. Erratum: Drug Saf 1999 Feb;20(2):146.
  5. Ved HS, Koenig ML, Dave JR, Doctor BP. Huperzine A, a potential therapeutic agent for dementia, reduces neuronal cell death caused by glutamate. Neuroreport 1997 Mar 3;8(4):963-8.
  6. Grunwald J, Raveh L, Doctor BP, Ashani Y. Huperzine A as a pretreatment candidate drug against nerve agent toxicity. Life Sci 1994;54(14):991-7.
  7. Sun QQ, Xu SS, Pan JL, Guo HM, Cao WQ. Huperzine-A capsules enhance memory and learning performance in 34 pairs of matched adolescent students. Acta Pharmacol Sin 1999 Jul;20(7):601-3.
  8. Matthews WS, Solan A, Barabas G. Cognitive functioning in Lesch-Nyhan syndrome. Dev Med Child Neurol 1995 Aug;37(8):715-22.

FREE Subscription

  • You're just getting started! We have published thousands of scientific health articles. Stay updated and maintain your health.

    It's free to your e-mail inbox and you can unsubscribe at any time.
    Loading Indicator