View source for Huperzine A

{{Short description|Chemical compound}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 461740300
| image = Huperzine A.png
| width = 200
| image2 = HuperzineA3d.png
| width2 = 200
| IUPAC_name = (1''R'',9''R'',13''E'')-1-Amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1.0<sup>2,7</sup>]trideca-2(7),3,10-trien-5-one
| synonyms = HupA
<!--Identifiers-->| ATC_prefix = N06
| ATC_suffix = 
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01928
| PubChem = 854026
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 78330
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 395280
| ChemSpiderID = 16736021
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = 0111871I23
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 102518-79-6
<!--Clinical data-->| tradename = 
| Drugs.com = 
| legal_AU = 
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = 
| legal_US = 
| routes_of_administration = [[By mouth]]
<!--Pharmacokinetic data-->| bioavailability = 
| protein_bound = 
| metabolism = 
| elimination_half-life = 10–14 hours<ref>{{cite journal | vauthors = Li YX, Zhang RQ, Li CR, Jiang XH | title = Pharmacokinetics of huperzine A following oral administration to human volunteers | journal = European Journal of Drug Metabolism and Pharmacokinetics | volume = 32 | issue = 4 | pages = 183–187 | date = 2007 | pmid = 18348466 | doi = 10.1007/BF03191002 | s2cid = 2702029 }}</ref>
| excretion = <!--Physical data-->
| density = 
| melting_point = 217
| melting_high = 219
| melting_notes = 
| solubility = <!--Chemical data-->
| C = 15
| H = 18
| N = 2
| O = 1
| smiles = C/C=C/1\[C@@H]2CC3=C([C@]1(CC(=C2)C)N)C=CC(=O)N3
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = ZRJBHWIHUMBLCN-YQEJDHNASA-N
}}

[[File:Huperzine A Life Extension.jpg|thumb|150px|Huperzine A capsules sold by the supplement company [[Biomedical Research & Longevity Society|Life Extension]], 200μg per capsule]]
[[File:Huperzine A in China.jpg|thumb|200px|Huperzine A pills in China, 50μg per tablet]]

'''Huperzine A''', a [[Lycopodium]] [[alkaloid]], was first isolated in 1983 from ''[[Huperzia serrata]]'',<ref>{{Cite journal | vauthors = Liu JS, Zhu YL, Yu CM, Zhou YZ, Han YY, Wu FW, Qi BF |year=1986 |title=The structures of huperzine A and B, two new alkaloids exhibiting marked anticholinesterase activity |journal=Canadian Journal of Chemistry |volume=64 |issue=4 |pages=837–839 | doi = 10.1139/v86-137 |bibcode=1986CaJCh..64..837L }}</ref><ref>{{cite patent | inventor = Yu CM, Tang XC, Liu JS, Han YY | assign = | gdate = 5 January 1993 | title = Huperzines and analogs. | country = US | number = 5,177,082 | url = https://patents.google.com/patent/US5177082A/en?oq=US5177082A }}</ref><ref>{{cite journal | vauthors = Yu CM, Calhoun LA, Konder RM, Grant AS | title = Huperzimine, a novel Lycopodium alkaloid from Huperzia serrata. | journal = Canadian Journal of Chemistry | date = 2014 | volume = 92 | issue = 5 | pages = 406–410 | doi = 10.1139/cjc-2013-0520 | bibcode = 2014CaJCh..92..406Y }}</ref> 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.<ref>{{cite journal | vauthors = Lim WH, Goodger JQ, Field AR, Holtum JA, Woodrow IE | title = Huperzine alkaloids from Australasian and southeast Asian Huperzia | journal = Pharmaceutical Biology | volume = 48 | issue = 9 | pages = 1073–1078 | date = September 2010 | pmid = 20731560 | doi = 10.3109/13880209.2010.485619 | doi-access = free }}</ref> 

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.<ref name="meta2013">{{cite journal | vauthors = Yang G, Wang Y, Tian J, Liu JP | title = Huperzine A for Alzheimer's disease: a systematic review and meta-analysis of randomized clinical trials | journal = PLOS ONE | volume = 8 | issue = 9 | pages = e74916 | date = 2013 | pmid = 24086396 | pmc = 3781107 | doi = 10.1371/journal.pone.0074916 | doi-access = free | bibcode = 2013PLoSO...874916Y }}</ref><ref name="cochranemeta">{{cite journal |vauthors=Li J, Wu HM, Zhou RL, Liu GJ, Dong BR |date=April 2008 |title=Huperzine A for Alzheimer's disease |journal=The Cochrane Database of Systematic Reviews |volume=CD005592 |issue=2 |pages=CD005592 |doi=10.1002/14651858.CD005592.pub2 |pmid=18425924 |veditors=Wu HM}}</ref> 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 [[Dietary supplement|nutritional supplement]] and marketed as a memory and concentration [[Nootropic|enhancer]].

==Adverse effects==
Huperzine A may present with mild [[Acetylcholine receptor|cholinergic]] side effects such as nausea, vomiting, and diarrhea.<ref name="cochranemeta" /> 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.<ref name="Natural Standard">{{cite web |title=Huperzine A |url=https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=764#safety |access-date=29 October 2014 |website=Natural Standard: The Authority on Integrative Medicine |publisher=Natural Standard}}</ref>

==Pharmacology==
Huperzine A is a reversible [[acetylcholinesterase inhibitor]]<ref>{{cite journal | vauthors = Wang R, Yan H, Tang XC | title = Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine | journal = Acta Pharmacologica Sinica | volume = 27 | issue = 1 | pages = 1–26 | date = January 2006 | pmid = 16364207 | doi = 10.1111/j.1745-7254.2006.00255.x | quote = Huperzine A (HupA), a novel alkaloid isolated from the Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase (AChE). | doi-access = free }}</ref><ref>{{cite book | url=https://books.google.com/books?id=a5AMBY9ekzcC&q=Huperzine&pg=PA191 | title=Herbs and Nutrients for the Mind: A Guide to Natural Brain Enhancers | publisher=Greenwood Publishing Group | vauthors = Meletis CD, Barke JE | date=2004 | pages=191 | isbn=978-0-275-98394-9}}</ref><ref name="Alzheimer 1996">{{cite journal | vauthors = Wang BS, Wang H, Wei ZH, Song YY, Zhang L, Chen HZ | title = Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer's disease: an updated meta-analysis | journal = Journal of Neural Transmission | volume = 116 | issue = 4 | pages = 457–465 | date = April 2009 | pmid = 19221692 | doi = 10.1007/s00702-009-0189-x | s2cid = 8655284 }}</ref><ref>{{cite journal  | vauthors = Tang XC, He XC, Bai DL | title=Huperzine A: A novel acetylcholinesterase inhibitor | journal=Drugs of the Future | date=1999 | volume=24 | issue=6 | pages=647 | doi=10.1358/dof.1999.024.06.545143 }}</ref> and [[NMDA receptor antagonist]]<ref>{{cite journal | vauthors = Coleman BR, Ratcliffe RH, Oguntayo SA, Shi X, Doctor BP, Gordon RK, Nambiar MP | title = [+]-Huperzine A treatment protects against N-methyl-D-aspartate-induced seizure/status epilepticus in rats | journal = Chemico-Biological Interactions | volume = 175 | issue = 1–3 | pages = 387–395 | date = September 2008 | pmid = 18588864 | doi = 10.1016/j.cbi.2008.05.023 | bibcode = 2008CBI...175..387C }}</ref> that crosses the [[blood–brain barrier]].<ref>{{cite journal | vauthors = Patocka J | title = Huperzine A--an interesting anticholinesterase compound from the Chinese herbal medicine | journal = Acta Medica | volume = 41 | issue = 4 | pages = 155–157 | date = 1998 | pmid = 9951045 | doi = 10.14712/18059694.2019.181 | doi-access = free }}</ref> [[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: [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1vot 1VOT]; [http://www.proteopedia.org/wiki/index.php/1vot see the 3D structure]).<ref>{{cite journal | vauthors = Raves ML, Harel M, Pang YP, Silman I, Kozikowski AP, Sussman JL | title = Structure of acetylcholinesterase complexed with the nootropic alkaloid, (-)-huperzine A | journal = Nature Structural Biology | volume = 4 | issue = 1 | pages = 57–63 | date = January 1997 | pmid = 8989325 | doi = 10.1038/nsb0197-57 | s2cid = 236518 }}</ref>

==Drug interactions==
Huperzine A may have [[Additive effect|additive effects]] if taken with drugs causing [[bradycardia]], such as [[beta-blocker]]s,<ref name="pepping">{{cite journal | vauthors = Pepping J | title = Huperzine A | journal = American Journal of Health-System Pharmacy | volume = 57 | issue = 6 | pages = 530, 533-530, 534 | date = March 2000 | pmid = 10754762 | doi = 10.1093/ajhp/57.6.530 | doi-access = free }}</ref> which may decrease heart rate. Theoretically, there may be possible additive cholinergic effects if huperzine A is taken with other [[acetylcholinesterase inhibitor]]s or [[cholinergic]] agents.<ref>{{cite journal | vauthors = Skolnick AA | title = Old Chinese herbal medicine used for fever yields possible new Alzheimer disease therapy | journal = JAMA | volume = 277 | issue = 10 | pages = 776 | date = March 1997 | pmid = 9052690 | doi = 10.1001/jama.1997.03540340010004 }}{{Failed verification|date=April 2025}}</ref>

==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.<ref name="Safety">{{cite journal | vauthors = Lallement G, Baille V, Baubichon D, Carpentier P, Collombet JM, Filliat P, Foquin A, Four E, Masqueliez C, Testylier G, Tonduli L, Dorandeu F | title = Review of the value of huperzine as pretreatment of organophosphate poisoning | journal = Neurotoxicology | volume = 23 | issue = 1 | pages = 1–5 | date = May 2002 | pmid = 12164543 | doi = 10.1016/S0161-813X(02)00015-3 | bibcode = 2002NeuTx..23....1L }}</ref>

==Synthesis==
Two scalable and efficient [[total synthesis|total syntheses]] of huperzine A have been reported.<ref>{{cite journal | vauthors = un MK, Wüstmann DJ, Herzon SB | title=A robust and scalable synthesis of the potent neuroprotective agent (−)-huperzine A | journal=Chemical Science | date=2011 | volume=2 | issue=11 | pages=2251–2253 | doi=10.1039/C1SC00455G | s2cid=98224866 }}</ref><ref>{{cite journal |  vauthors = Tudhope SR, Bellamy JA, Ball A, Rajasekar D, Azadi-Ardakani M, Meera HS, Gnanadeepam JM, Saiganesh R, Gibson F, He L, Behrens CH | title=Development of a Large-Scale Synthetic Route to Manufacture (−)-Huperzine A | journal=Organic Process Research & Development | date=2012 | volume=16 | issue=4 | pages=635–642 | doi=10.1021/op200360b }}</ref>

== History ==
In 1989, a research study found<ref>{{cite journal |vauthors=Ayer WA, Browne LM, Orszanska H, Valenta Z |date=October 1989 |title=Alkaloids of ''Lycopodium selago''. On the identity of selagine with huperzine A and the structure of a related alkaloid. |journal=Canadian Journal of Chemistry |volume=67 |issue=10 |pages=1538–1540 |bibcode=1989CaJCh..67.1538A |doi=10.1139/v89-234}}</ref> that the chemical structure of the alkaloid selagine reported in 1960 from a study of ''Lycopodium slago L.''<ref>{{cite journal |vauthors=Valenta Z, Yoshimura H, Rogers EF, Ternbah M, Wiesner K |date=January 1960 |title=The structure of selagine. |journal=Tetrahedron Letters |volume=1 |issue=31 |pages=26–33 |doi=10.1016/S0040-4039(01)99300-1}}</ref> (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 [[Neurodegenerative disease|neurodegeneration]] such as [[Alzheimer's disease]],<ref name="Zangara2003">{{cite journal |vauthors=Zangara A |date=June 2003 |title=The psychopharmacology of huperzine A: an alkaloid with cognitive enhancing and neuroprotective properties of interest in the treatment of Alzheimer's disease |journal=Pharmacology, Biochemistry, and Behavior |volume=75 |issue=3 |pages=675–686 |doi=10.1016/S0091-3057(03)00111-4 |pmid=12895686 |s2cid=36435892}}</ref><ref name="r1">{{cite journal |vauthors=Bai DL, Tang XC, He XC |date=March 2000 |title=Huperzine A, a potential therapeutic agent for treatment of Alzheimer's disease |journal=Current Medicinal Chemistry |volume=7 |issue=3 |pages=355–374 |doi=10.2174/0929867003375281 |pmid=10637369}}</ref> 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 [[Umbrella review|systematic review of systematic reviews]],<ref>{{cite journal |vauthors=Laver K, Dyer S, Whitehead C, Clemson L, Crotty M |date=April 2016 |title=Interventions to delay functional decline in people with dementia: a systematic review of systematic reviews |journal=BMJ Open |volume=6 |issue=4 |pages=e010767 |doi=10.1136/bmjopen-2015-010767 |pmc=4854009 |pmid=27121704}}</ref> huperzine A was associated with a [[Effect size|standardized mean difference]] of 1.48 ([[Confidence interval|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,<ref>{{cite journal |vauthors=Fan F, Liu H, Shi X, Ai Y, Liu Q, Cheng Y |date=2022-02-01 |title=The Efficacy and Safety of Alzheimer's Disease Therapies: An Updated Umbrella Review |journal=Journal of Alzheimer's Disease |volume=85 |issue=3 |pages=1195–1204 |doi=10.3233/JAD-215423 |pmid=34924395 |s2cid=245311001}}</ref> huperzine A was associated with broad benefits to dementia patients' cognitive functioning, but the degree of [[Study heterogeneity|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 poisoning|organophosphate nerve agent poisoning]] by preventing damage to the [[central nervous system]] caused by such agents.<ref name="Lallement_2002">{{cite journal |vauthors=Lallement G, Baille V, Baubichon D, Carpentier P, Collombet JM, Filliat P, Foquin A, Four E, Masqueliez C, Testylier G, Tonduli L, Dorandeu F |date=May 2002 |title=Review of the value of huperzine as pretreatment of organophosphate poisoning |journal=Neurotoxicology |volume=23 |issue=1 |pages=1–5 |doi=10.1016/s0161-813x(02)00015-3 |pmid=12164543|bibcode=2002NeuTx..23....1L }}</ref><ref name="Liu_2005">{{cite journal |vauthors=Liu L, Sun JX |date=March 2005 |title=[Advances on study of organophosphate poisoning prevented by Huperzine A] |url=https://europepmc.org/article/med/15952670 |journal=Wei Sheng Yan Jiu = Journal of Hygiene Research |language=Chinese |volume=34 |issue=2 |pages=224–226 |pmid=15952670}}</ref>

== References ==
{{Reflist}}

== External links ==
* [http://www.proteopedia.org/wiki/index.php/AChE_inhibitors_and_substrates AChE inhibitors and substrates] in [[Proteopedia]]

{{Antidementia}}
{{Acetylcholine metabolism and transport modulators}}
{{Ionotropic glutamate receptor modulators}}

[[Category:Acetylcholinesterase inhibitors]]
[[Category:Enones]]
[[Category:Conjugated dienes]]
[[Category:2-Pyrones]]
[[Category:NMDA receptor antagonists]]
[[Category:Nootropics]]
[[Category:Sesquiterpene alkaloids]]
[[Category:Treatment of Alzheimer's disease]]