Huperzine A

Huperzine A, a Lycopodium alkaloid, was first isolated in 1983 from Huperzia serrata,^[2][3][4] 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.^[5]

Huperzine A

Clinical data
Other names	HupA
Routes of administration	By mouth
ATC code	N06
Pharmacokinetic data
Elimination half-life	10–14 hours[1]
Identifiers
IUPAC name (1R,9R,13E)-1-Amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1.02,7]trideca-2(7),3,10-trien-5-one
CAS Number	102518-79-6 N
PubChem CID	854026
DrugBank	DB01928 Y
ChemSpider	16736021 Y
UNII	0111871I23
ChEBI	CHEBI:78330 N
ChEMBL	ChEMBL395280 Y
CompTox Dashboard (EPA)	DTXSID8046038
ECHA InfoCard	100.132.430
Chemical and physical data
Formula	C15H18N2O
Molar mass	242.322 g·mol−1
3D model (JSmol)	Interactive image
Melting point	217 to 219 °C (423 to 426 °F)
SMILES C/C=C/1\[C@@H]2CC3=C([C@]1(CC(=C2)C)N)C=CC(=O)N3
InChI InChI=1S/C15H18N2O/c1-3-11-10-6-9(2)8-15(11,16)12-4-5-14(18)17-13(12)7-10/h3-6,10H,7-8,16H2,1-2H3,(H,17,18)/b11-3+/t10-,15+/m0/s1 Y Key:ZRJBHWIHUMBLCN-YQEJDHNASA-N Y
NY (what is this?)  (verify)

Huperzine A capsules sold by the supplement company Life Extension, 200μg per capsule

Huperzine A pills in China, 50μg per tablet

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.^[6][7]

Huperzine A inhibits acetylcholinesterase, the enzyme responsible for breaking down the neurotransmitter acetylcholine (ACh), and is also a weak NMDA receptor antagonist with poor affinity. It crosses the blood-brain barrier and is widely available as an over the counter nutritional supplement, marketed as a memory and concentration enhancer.

Adverse effects

Huperzine A may present with mild cholinergic side effects such as nausea, vomiting, and diarrhea.^[7] Slight muscle twitching and slurred speech might also occur, as well as hypersalivation and sweating. The use of huperzine A during pregnancy and lactation is not recommended due to the lack of sufficient safety data.^[8]

Pharmacology

Huperzine A is a potent, highly specific, reversible acetylcholinesterase inhibitor^{[9][10][11][12]}, with IC50 binding affinity of ~82 nM^[13]. It is also a weak NMDA receptor antagonist^[14], with IC50 of ~65,000-82,000 nM^[15] (65-82 µM); due to this relatively low affinity, huperzine A is unlikely to produce significant NMDA receptor blockade at clinically relevant concentrations in humans. Huperzine A readily crosses the blood-brain barrier and demonstrates central nervous system activity at therapeutic doses as low as 100 mcg in humans.^[16]

Acetylcholinesterase is an enzyme that catalyzes the breakdown of choline-based neurotransmitters, particularly acetylcholine (ACh), which plays a critical role in memory, learning, and behavior. The structure of the complex of huperzine A with acetylcholinesterase has been determined by X-ray crystallography (PDB code: 1VOT; see the 3D structure).^[17]

Drug interactions

Huperzine A may have additive effects if taken with drugs causing bradycardia, such as beta-blockers,^[18] 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.^[19]

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.^[20]

Synthesis

Two scalable and efficient total syntheses of huperzine A have been reported.^[21][22]

History

In 1989, a research study found^[23] that the chemical structure of the alkaloid selagine reported in 1960 from a study of Lycopodium slago L.^[24] (analyzed using 60-MHz NMR) was identical to that of Huperzine A.

Research

Effects

Huperzine A has been investigated as a possible treatment for diseases characterized by neurodegeneration such as Alzheimer's disease,^[25][26] 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,^[27] 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,^[28] 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.

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 caused by such agents.^[29][30]