Huperzine A, a

Lycopodium ''Lycopodium'' (from Ancient Greek ''lykos'', wolf and ''podion'', diminutive of ''pous'', foot) is a genus of clubmosses, also known as ground pines or creeping cedars, in the family Lycopodiaceae. Two very different circumscriptions of the gen ...

alkaloid Alkaloids are a broad class of natural product, naturally occurring organic compounds that contain at least one nitrogen atom. Some synthetic compounds of similar structure may also be termed alkaloids. Alkaloids are produced by a large varie ...

, was first isolated in 1983 from '' Huperzia serrata'', a plant used in Chinese folk medicine. Huperzine A also exists in other Huperzia species, including ''H. elmeri'', ''H. carinat'', and ''H. aqualupian'' with varying quantities. Huperzine A has been investigated as a treatment for neurological conditions such as

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

, but a 2013

meta-analysis Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...

of those studies concluded that they were of poor methodological quality and the findings should be interpreted with caution. Huperzine A inhibits the breakdown of the

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

(ACh) by the enzyme

acetylcholinesterase Acetylcholinesterase (HUGO Gene Nomenclature Committee, HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme th ...

. It is also an antagonist of the

NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...

. It is commonly available over the counter as a

nutritional supplement A dietary supplement is a manufactured product intended to supplement a person's diet by taking a pill, capsule, tablet, powder, or liquid. A supplement can provide nutrients either extracted from food sources, or that are synthetic ( ...

and marketed as a memory and concentration enhancer.

Adverse effects

Huperzine A may present with mild

cholinergic Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word " choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cation ...

side effects such as nausea, vomiting, and diarrhea. Slight muscle twitching and slurred speech might also occur, as well as

hypersalivation Hypersalivation or hypersialosis is the excessive production of saliva. It has also been defined as increased amount of saliva in the mouth, which may also be caused by decreased clearance of saliva.Medscape > HypersalivationBy Erica Brownfield. P ...

and sweating. The use of huperzine A during pregnancy and lactation is not recommended due to the lack of sufficient safety data.

Pharmacology

Huperzine A is a reversible

acetylcholinesterase inhibitor Acetylcholinesterase inhibitors (AChEIs) also often called cholinesterase inhibitors, inhibit the enzyme acetylcholinesterase from breaking down the neurotransmitter acetylcholine into choline and acetate, thereby increasing both the level an ...

and

NMDA receptor antagonist NMDA receptor antagonists are a class of drugs that work to receptor antagonist, antagonize, or inhibit the action of, the NMDA, ''N''-Methyl-D-aspartate receptor (NMDA receptor, NMDAR). They are commonly used as anesthetics for humans and anima ...

that crosses the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

Acetylcholinesterase Acetylcholinesterase (HUGO Gene Nomenclature Committee, HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme th ...

is an enzyme that catalyzes the breakdown of the neurotransmitter ACh and other choline esters that function as neurotransmitters. The structure of the complex of huperzine A with acetylcholinesterase has been determined by

X-ray crystallography X-ray crystallography is the experimental science of determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to Diffraction, diffract in specific directions. By measuring th ...

(PDB code
1VOTsee the 3D structure
.

Drug interactions

Huperzine A may have additive effects if taken with drugs causing

bradycardia Bradycardia, also called bradyarrhythmia, is a resting heart rate under 60 beats per minute (BPM). While bradycardia can result from various pathological processes, it is commonly a physiological response to cardiovascular conditioning or due ...

, such as

beta-blocker Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms ( arrhythmia), and to protect the heart from a second heart attack after a first heart attack (secondary prevention) ...

s, which may decrease heart rate. Theoretically, there may be possible additive cholinergic effects if huperzine A is taken with other

s or

agents.

Safety

Huperzine A, in spite of the possible cholinergic side effects, seems to have a wide margin of safety.

Toxicology Toxicology is a scientific discipline, overlapping with biology, chemistry, pharmacology, and medicine, that involves the study of the adverse effects of chemical substances on living organisms and the practice of diagnosing and treating ex ...

studies show huperzine A to be non-toxic even when administered at 50-100 times the human therapeutic dose. The extract is active for 6 hours at a dose of 2 μg/kg with no remarkable side effects.

Synthesis

Two scalable and efficient total syntheses of huperzine A have been reported.

History

In 1989, a research study found that the chemical structure of the alkaloid selagine reported in 1960 from a study of ''Lycopodium slago L.'' (analyzed using 60-MHz

NMR Nuclear magnetic resonance (NMR) is a physical phenomenon in which atomic nucleus, nuclei in a strong constant magnetic field are disturbed by a weak oscillating magnetic field (in the near and far field, near field) and respond by producing ...

) was identical to that of Huperzine A.

Research

Effects

Huperzine A has been investigated as a possible treatment for diseases characterized by

neurodegeneration A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their cell death, death. Neurodegenerative diseases include amyotrophic lateral sc ...

such as

, and there is some evidence from small-scale studies that it can benefit cognitive functioning, global clinical status, and ability to engage in

activities of daily living Activities of daily living (ADLs) is a term used in healthcare to refer to an individual's daily self-care activities. Health professionals often use a person's ability or inability to perform ADLs as a measure of their Performance status, functi ...

(ADLs) among individuals with the disease. In a 2016 systematic review of systematic reviews, huperzine A was associated with a standardized mean difference of 1.48 ( 95% CI, 0.95-2.02) compared to placebo on measures of ADL among people with dementia, but the evidence was very low-quality and uncertain. In a 2022 umbrella review, huperzine A was associated with broad benefits to dementia patients' cognitive functioning, but the degree of

heterogeneity Homogeneity and heterogeneity are concepts relating to the uniformity of a substance, process or image. A homogeneous feature is uniform in composition or character (i.e., color, shape, size, weight, height, distribution, texture, language, i ...

in measurements and outcomes of the reviewed studies indicated

publication bias In published academic research, publication bias occurs when the outcome of an experiment or research study biases the decision to publish or otherwise distribute it. Publishing only results that show a Statistical significance, significant find ...

toward huperzine A benefit.

Use in organophosphate poisoning

Huperzine A might be useful in the treatment of organophosphate nerve agent poisoning by preventing damage to the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

caused by such agents.

References

External links

AChE inhibitors and substrates
in Proteopedia {{Ionotropic glutamate receptor modulators Acetylcholinesterase inhibitors Enones Conjugated dienes 2-Pyrones NMDA receptor antagonists Nootropics Sesquiterpene alkaloids Treatment of Alzheimer's disease