# Huperzine A

Huperzine A, a Lycopodium alkaloid, was first isolated in 1983 ( ≈ 0.010% yield) from club moss Huperzia serrata (Thunb.) Trevis. [1, 2, ef. 3], a plant used in Chinese folk medicine. In 1989, Ayer group found[4] that the chemical structure of the alkaloid Selagine reported in 1960 from a study of Lycopodium slago L. [5] (analyzed using 60-MHz NMR) was identical to that of Huperzine A.
Huperzine A also exists in other Huperzia species, including H. elmeri, H. carinat, and H. aqualupian with varying quantities (refer to current reference: Lim WH et al., September 2010, "Huperzine alkaloids from Australasian and southeast Asian Huperzia").
References:
1. Liu JS, Zhu YL, Yu CM, Zhou YZ, Han YY, Wu FW, Qi, BF (1986). “The structures of huperzine A and B, two new alkaloids exhibiting marked anticholinesterase activity“. Canadian Journal of Chemistry. 64: 837-839. doi:10.1139/v86-137.
2. Yu CM, Tang XC, Liu JS, Han YY (1993). “Huperzines and analogs”. US Patent No. 5,177,082. Available from https://ppubs.uspto.gov/pubwebapp/static/pages/ppubsbasic.html
3. Yu CM, Calhoun LA, Konder RM, Grant AS (2014). “Huperzimine, a novel Lycopodium alkaloid from Huperzia serrat”. Canadian Journal of Chemistry. 92: 406-410. dx.doi.org/10.1139/cjc-2013-0520
4. Ayer WA, Browne LM, Orszanska H, Valenta Z (1989). “Alkaloids of Lycopodium selago. On the identity of selagine with huperzine A and the structure of a related alkaloid”. Canadian Journal of Chemistry.67:1538-1540. https://doi.org/10.1139/v89-234
5. Valenta Z, Yoshimura H, Rogers EF, Ternbah M, Wiesner K (1960).”The Structure of Selagine”.Tetrahedron Letters. 10: 26.
(Note: I would highly appreciate it if some experienced person could help me to complete this revision and insert the corresponding references cited therein.)
is a naturally-occurring sesquiterpene alkaloid compound found in the firmoss Huperzia serrata 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, but a 2013 meta-analysis 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 (ACh) by the enzyme acetylcholinesterase. It is also an antagonist of the NMDA-receptor. It is commonly available over the counter as a nutritional supplement and marketed as a memory and concentration enhancer.
Huperzine A has also been noted to help induce lucid dreaming.

## Pharmacological effects

Huperzine A is extracted from Huperzia serrata. It is a reversible acetylcholinesterase inhibitor and NMDA receptor antagonist that crosses the blood–brain barrier. Acetylcholinesterase 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 (PDB code: 1VOT; see the 3D structure).
Huperzine A has been investigated as a possible treatment for diseases characterized by neurodegeneration such as Alzheimer's disease, 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 (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 in measurements and outcomes of the reviewed studies indicated publication bias toward huperzine A benefit.

## 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, such as beta-blockers, which may decrease heart rate. Theoretically, there may be possible additive cholinergic effects if huperzine A is taken with other acetylcholinesterase inhibitors or cholinergic 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 by preventing damage to the central nervous system caused by such agents.

## Synthesis

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