Huperzine A is a naturally occurring

sesquiterpene Sesquiterpenes are a class of terpenes that consist of three isoprene units and often have the molecular formula C15H24. Like monoterpenes, sesquiterpenes may be cyclic or contain rings, including many unique combinations. Biochemical modificat ...

alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar ...

compound found in the

firmoss ''Huperzia'' is a genus of lycophyte plants, sometimes known as the firmosses or fir clubmosses; the ''Flora of North America'' calls them gemma fir-mosses. This genus was originally included in the related genus ''Lycopodium'', from which it dif ...

Huperzia serrata ''Huperzia serrata'', the toothed clubmoss, is a plant known as a firmoss which contains the acetylcholinesterase inhibitor huperzine A Huperzine A is a naturally occurring sesquiterpene alkaloid compound found in the firmoss ''Huperzia serr ...

'' and in varying quantities in other food ''Huperzia'' species, including ''H. elmeri'', ''H. carinat'', and ''H. aqualupian''. Huperzine A has been investigated as a treatment for neurological conditions such as

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

, but a

meta-analysis A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting me ...

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

acetylcholine Acetylcholine (ACh) is an organic chemical 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. Part ...

by the enzyme

acetylcholinesterase Acetylcholinesterase (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 Enzymes () are proteins that a ...

. It is commonly available over the counter as a nutrient supplement, and is marketed as a cognitive enhancer for improving memory and concentration.

Pharmacological effects

Huperzine A is extracted from ''

''. It 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 and ...

and

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

antagonist that crosses the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...

Acetylcholinesterase Acetylcholinesterase (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 Enzymes () are proteins that a ...

is an enzyme that catalyzes the breakdown of the neurotransmitter acetylcholine and of some 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 determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...

(PDB code
1VOTsee the 3D structure
. For some years, huperzine A has been investigated as a possible treatment for diseases characterized by neurodegeneration, particularly

. A 2013 meta-analysis found that huperzine A may be efficacious in improving cognitive function, global clinical status, and activities of daily living for individuals with Alzheimer's disease. However, due to the poor size and quality of the clinical trials reviewed, huperzine A should not be recommended as a treatment for Alzheimer's disease unless further high quality studies confirm such findings. Huperzine A is also marketed as a dietary supplement with claims made for its ability to improve memory and mental function, based on positive results from animal studies and clinical research. Huperzine A has also been noted to help induce

lucid dreaming A lucid dream is a type of dream in which the dreamer becomes aware that they are dreaming while dreaming. During a lucid dream, the dreamer may gain some amount of control over the dream characters, narrative, or environment; however, this is n ...

. Most notably in the sports industry, Huperzine is used as a sublingual dietary supplement to increase muscular contraction and force output during weighted strength training by increasing the amount of acetylcholine in the neuromuscular junction, allowing more stimulation of ACh receptors

Adverse effects

Huperzine A may present with mild cholinergic side effects such as nausea, vomiting, and diarrhea. Slight muscle twitching and slurred speech might also occur, as well as excessive saliva excretion and sweating. The use of huperzine A during pregnancy and lactation is not recommended due to the lack of sufficient safety data.

Drug interactions

Huperzine A may have additive effects if taken with drugs causing

bradycardia Bradycardia (also sinus bradycardia) is a slow resting heart rate, commonly under 60 beats per minute (BPM) as determined by an electrocardiogram. It is considered to be a normal heart rate during sleep, in young and healthy or elderly adults, a ...

, such as

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

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

s or

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. F ...

agents.

Safety

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

Other possible uses

Huperzine A might be useful in the treatment of organophosphate nerve agent poisoning, preventing damage to the central nervous system caused by such agents.

Synthesis

Two scalable and efficient

total syntheses Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes ...

of huperzine A have been reported.

References

External links

AChE inhibitors and substrates
in

Proteopedia Proteopedia is a wiki, 3D encyclopedia of proteins and other molecules. The site contains a page for every entry in the Protein Data Bank (>130,000 pages), as well as pages that are more descriptive of protein structures in general such as acetylc ...

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