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Huperzine-A is a cognitive enhancer that inhibits an enzyme that degrades the learning neurotransmitter, acetylcholine; due to this, a relative increase occurs. It belongs to the cholinergics class of molecules, and may be useful in fighting cognitive decline in the elderly. May need to be cycled.

Our evidence-based analysis on huperzine-a features 21 unique references to scientific papers.

Research analysis led by and reviewed by the Examine team.
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Research Breakdown on Huperzine-A

1Structure and Sources


Huperzine-A is a compound found in the plant families of Huperziaceae, Lycopodiaceae, and Selaginella.[1][2] It is normally extracted from the plants of the Huperziaceae family, but can be propogated in other cell lines for cheap mass production.[3] This synthetic Huperzine-A has bioequivlance to the natural version.

Its chemical structure is a pyridone moiety fused to a benzo{3,3,1}ring system with a ethylidene group attached to it. The (-)Huperzine stereoisomer is more bioactive than the (+)Huperzine Isomer.[2][4]


Huperzine-B is a congener (like compound) to that of Huperzine-A with a similar pharmacodynamic profile. Huperzine-B is less potent acutely[5] but has a longer dissiciation and subsequently a greater potential safety index and therapeutic index.[6] It is also an NMDA antagonist[5] and neural anti-oxidant.[7] It is currently being chemically modified to increase potency without risking the longer dissociation.[8][9]


Orally administered tablets tend to appear in the blood in 15 minutes or less and peak at a variable time around 70 minutes post-ingestion.[10][11] It shows a biphasic response of a rapid serum increase followed by a slower excretion rate[10] and has an alpha and beta half-life of 21.13+/-7.28 and 716.25+/-130.18 min, respectively.[11] These half-lifes were noted to be different in another study though, in which Huperzine-A fitted a one-compartment model at 0.99mg.[10]

It appears in the cerebrospinal fluid and is easily able to cross the blood-brain barrier.[2]


3.1Cholinergic Neurotransmission

Huperzine-A's most renowned action is that of an acetylcholinesterase inhibitor. Specifically, it can inhibit the G4 isoform of acetylcholinesterase which is highly prevalent in mammalian brains.[12] It is of greater or equal potency to other acetylcholinesterase inhibitors such as Tacrine or Rivastigmine.[12] It has a high affinity for acetylcholinesterase as an inhibitor, and a slow dissociation constant which enables a long active half-life.[13]

It may be preferable for usage as a cholinergic since it has been reported to have less cholinergic-related side-effects,[14] possibly through its high affinity for brain G4 acetylcholine resulting in less availability for systemic butrylcholine inhibition, which leads to various systemic effects which may be seen as side effects.[15][16]


In addition to acetylcholinesterase inhibition, it can also be seen as neuroprotective against glutamate,[17] beta-amyloid pigmentation,[18] and H2O2-induced toxicity.[19] 

Huperzine-A can also block the NMDA receptor ion channel without psychomimetic side-effects.[20]


Huperzine-A is able to promote proliferation of hippocampal neural stem cells (NSCs) at a concentration of 1μM for 48 hours (which is more potent than 10-100μM) to 125% of control secondary to activating the ERK pathway,[21] and this neurogenesis was confimed in vivo with injections of 0.2mg/kg of huperzine-A for 4 weeks (about a 25% increase in BrdU stained cells, affecting both newborn and adult mice).[21]

Appears to promote neurogenesis in biologically relevant dosages

4Safety and Toxicity

A study in rats concluded that the LD50 (dose needed to acutely kill half a population of rats) was 2-4mg/kg bodyweight in females and >4mg/kg in males whereas others pinpoint the level at around 3mg/kg bodyweight over a longer period (180 days).[13] The NOAEL (No Observable Adverse Effects Limit) is postulated to be 1mg/kg for females rats, 3mg/kg for males rats, and 0.1mg/kg for canines. No toxicity data for humans currently exists.


  1. ^ Howes MJ, Perry NS, Houghton PJ. Plants with traditional uses and activities, relevant to the management of Alzheimer's disease and other cognitive disorders. Phytother Res. (2003)
  2. ^ a b c Ha GT, Wong RK, Zhang Y. Huperzine a as potential treatment of Alzheimer's disease: an assessment on chemistry, pharmacology, and clinical studies. Chem Biodivers. (2011)
  3. ^ Ma X, Gang DR. In vitro production of huperzine A, a promising drug candidate for Alzheimer's disease. Phytochemistry. (2008)
  4. ^ Total Synthesis of (−)-Huperzine A.
  5. ^ a b Wang XD, et al. Comparison of the effects of cholinesterase inhibitors on {3H}MK-801 binding in rat cerebral cortex. Neurosci Lett. (1999)
  6. ^ Rajendran V, et al. Synthesis of more potent analogues of the acetylcholinesterase inhibitor, huperzine B. Bioorg Med Chem Lett. (2002)
  7. ^ Zhang HY, Tang XC. Huperzine B, a novel acetylcholinesterase inhibitor, attenuates hydrogen peroxide induced injury in PC12 cells. Neurosci Lett. (2000)
  8. ^ Feng S, et al. Bis-huperzine B: highly potent and selective acetylcholinesterase inhibitors. J Med Chem. (2005)
  9. ^ He XC, et al. Study on dual-site inhibitors of acetylcholinesterase: Highly potent derivatives of bis- and bifunctional huperzine B. Bioorg Med Chem. (2007)
  10. ^ a b c Qian BC, et al. Pharmacokinetics of tablet huperzine A in six volunteers. Zhongguo Yao Li Xue Bao. (1995)
  11. ^ a b Li YX, et al. Pharmacokinetics of huperzine A following oral administration to human volunteers. Eur J Drug Metab Pharmacokinet. (2007)
  12. ^ a b Effects of huperzine A on acetylcholinesterase isoforms in vitro: comparison with tacrine, donepezil, rivastigmine and physostigmine.
  13. ^ a b Chemistry, Pharmacology, and Clinical Efficacy of the Chinese Nootropic Agent Huperzine A.
  14. ^ Development of huperzine A and B for treatment of Alzheimer’s disease.
  15. ^ Boudinot E, et al. Effects of acetylcholinesterase and butyrylcholinesterase inhibition on breathing in mice adapted or not to reduced acetylcholinesterase. Pharmacol Biochem Behav. (2005)
  16. ^ Lane RM, Potkin SG, Enz A. Targeting acetylcholinesterase and butyrylcholinesterase in dementia. Int J Neuropsychopharmacol. (2006)
  17. ^ Ved HS, et al. Huperzine A, a potential therapeutic agent for dementia, reduces neuronal cell death caused by glutamate. Neuroreport. (1997)
  18. ^ Huperzine A regulates amyloid precursor protein processing via protein kinase C and mitogen-activated protein kinase pathways in neuroblastoma SK-N-SH cells over-expressing wild type human amyloid precursor protein 695.
  19. ^ Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine.
  20. ^ The NMDA receptor ion channel: a site for binding of Huperzine A.
  21. ^ a b Ma T, et al. Huperzine A promotes hippocampal neurogenesis in vitro and in vivo. Brain Res. (2013)