Chinese Clubmoss

The plant is qian ceng ta (“thousand-layer pagoda”). Its recorded use traces to the Tang dynasty, when the dried whole plant was decocted mainly for rheumatism, colds and flu, and to “relax the muscles and tendons” ^{1Reference 1Ma X et al. · 2007ReviewHuperzine A from Huperzia species — an ethnopharmacological review — reviewView study →}.

Later Chinese practice extended it to bruises, sprains, poor circulation and swelling. In the modern era it has also been used for organophosphate poisoning, myasthenia gravis, schizophrenia and Alzheimer’s disease ^{1,32Reference 1Ma X et al. · 2007ReviewHuperzine A from Huperzia species — an ethnopharmacological review — reviewView study →Reference 32Xu M et al. · 2019ReviewEthnopharmacology of the club moss subfamily Huperzioideae — reviewView study →}.

Huperzine A is a licensed Alzheimer’s drug in China ^{1Reference 1Ma X et al. · 2007ReviewHuperzine A from Huperzia species — an ethnopharmacological review — reviewView study →}. It is a reversible acetylcholinesterase inhibitor that crosses into the brain, working on the same principle as donepezil or galantamine ^{1,8Reference 1Ma X et al. · 2007ReviewHuperzine A from Huperzia species — an ethnopharmacological review — reviewView study →Reference 8Qian ZM · 2014ReviewHuperzine A: is it an effective disease-modifying drug for Alzheimer’s disease? — reviewView study →}.

A 2013 systematic review and meta-analysis of 20 RCTs (1,823 participants) found improvements in cognition (MMSE, Hasegawa and Wechsler scales) and in activities of daily living compared with placebo. Most of the included trials carried a high risk of bias ^{4Reference 4Yang G et al. · 2013Meta-analysisHuperzine A for Alzheimer’s disease: a systematic review and meta-analysis of randomised clinical trials — meta-analysisView study →}.

In an 8-week multicentre Chinese RCT of 0.2 mg twice daily, 58% of treated patients improved, against 36% on placebo ^{5Reference 5Xu SS et al. · 1995RCTEfficacy of tablet huperzine-A on memory, cognition, and behavior in Alzheimer’s disease — randomised controlled trialView study →}.

The US Alzheimer’s Disease Cooperative Study Phase II trial randomised 210 people to placebo or huperzine A at 200 or 400 µg twice daily. At 200 µg twice daily, the primary endpoint (ADAS-Cog at 16 weeks) did not change. At 400 µg twice daily, ADAS-Cog improved at 11 weeks, but the difference at 16 weeks was not significant ^{2Reference 2Rafii MS et al. · 2011RCTA phase II trial of huperzine A in mild to moderate Alzheimer disease — randomised controlled trialView study →}.

A 2008 Cochrane review found six trials with 454 patients, only one of adequate quality, and judged the evidence inadequate for a recommendation ^{3Reference 3Li J et al. · 2008Systematic reviewHuperzine A for Alzheimer’s disease — systematic review (Cochrane)View study →}. A Cochrane review of mild cognitive impairment found no eligible trials ^{20Reference 20Yue J et al. · 2012Systematic reviewHuperzine A for mild cognitive impairment — systematic review (Cochrane)View study →}. An overview of systematic reviews concluded that huperzine A benefits cognition and daily function in Alzheimer’s disease, with insufficient evidence elsewhere ^{7Reference 7Ghassab-Abdollahi N et al. · 2021Systematic reviewThe effects of Huperzine A on dementia and mild cognitive impairment: an overview of systematic reviews — systematic reviewView study →}.

Gap: the positive data are dominated by short, biased Chinese trials; the one rigorous Western trial was negative on its primary endpoint, and no trial has tested long-term or disease-modifying outcomes.

The cholinergic system contributes to the memory and thinking problems of schizophrenia, and huperzine A has been tested as an add-on to antipsychotics. A 2016 systematic review and meta-analysis pooled 12 RCTs (n=1,117, lasting about 12 weeks on average). Huperzine A outperformed comparators on memory quotient and on several intelligence and executive-function measures ^{9Reference 9Zheng W et al. · 2016Meta-analysisAdjunctive huperzine A for cognitive deficits in schizophrenia: a systematic review and meta-analysis — meta-analysisView study →}.

Total scores on psychiatric symptom scales also improved, and dropout and adverse events were similar between groups ^{9Reference 9Zheng W et al. · 2016Meta-analysisAdjunctive huperzine A for cognitive deficits in schizophrenia: a systematic review and meta-analysis — meta-analysisView study →}. Every included trial was conducted in China, and none has been repeated in a Western population ^{9Reference 9Zheng W et al. · 2016Meta-analysisAdjunctive huperzine A for cognitive deficits in schizophrenia: a systematic review and meta-analysis — meta-analysisView study →}.

Huperzine A suppresses seizures across a range of rodent models: pentylenetetrazole, NMDA-induced status epilepticus and genetic absence epilepsy, among others ^{10,11,12,13Reference 10Gersner R et al. · 2015AnimalHuperzine A prophylaxis against pentylenetetrazole-induced seizures in rats is associated with increased cortical inhibition — rat in vivoView study →Reference 11Coleman BR et al. · 2008AnimalColeman BR, Ratcliffe RH, Oguntayo SA, et al. (2008). [+]-Huperzine A treatment protects against N-methyl-D-aspartate-induced seizure/status epilepticus in rats — rat in vivo. Chem Biol Interact. https://pubmed.ncbi.nlm.nih.gov/18588864/View study →Reference 12Casillas-Espinosa PM et al. · 2024AnimalHuperzine A suppresses absence seizures in the genetic absence epilepsy rat from Strasbourg (GAERS) model — rat in vivoView study →Reference 13Wang Y et al. · 2025AnimalHuperzine A attenuates epileptic seizures via enhancing dCA1-projecting septal cholinergic transmission — mouse in vivoView study →}. The effect appears to involve both cholinergic signalling and stronger GABA-mediated inhibition in the cortex ^{10,13Reference 10Gersner R et al. · 2015AnimalHuperzine A prophylaxis against pentylenetetrazole-induced seizures in rats is associated with increased cortical inhibition — rat in vivoView study →Reference 13Wang Y et al. · 2025AnimalHuperzine A attenuates epileptic seizures via enhancing dCA1-projecting septal cholinergic transmission — mouse in vivoView study →}. In the pentylenetetrazole rat model it raised the threshold to the first seizure jerk and increased measured cortical inhibition ^{10Reference 10Gersner R et al. · 2015AnimalHuperzine A prophylaxis against pentylenetetrazole-induced seizures in rats is associated with increased cortical inhibition — rat in vivoView study →}.

In the genetic absence epilepsy (GAERS) rat model it strongly suppressed absence seizures, though briefly ^{12Reference 12Casillas-Espinosa PM et al. · 2024AnimalHuperzine A suppresses absence seizures in the genetic absence epilepsy rat from Strasbourg (GAERS) model — rat in vivoView study →}. It has also been proposed as an anticonvulsant for people with Alzheimer’s disease, who are prone to seizures ^{14Reference 14Damar U et al. · 2017ReviewHuperzine A: a promising anticonvulsant, disease modifying, and memory enhancing treatment option in Alzheimer’s disease — reviewView study →}.

An extended-release huperzine A drug, SPN-817, is in Phase 2 trials in adults with focal-onset seizures and with treatment-resistant epilepsy ^{35,36Reference 35Supernus Pharmaceuticals · 2023Safety and Tolerability Study of SPN-817 (huperzine A, extended release) in Adult Patients With Treatment Resistant Epilepsy — registered trial, Phase 2View study →Reference 36Supernus Pharmaceuticals · 2024RCTRENAISSANCE 2: SPN-817 Phase 2, Double-Blind, Placebo-Controlled Study in Adults With Focal Onset Seizures — registered trial, Phase 2View study →}.

Gap: all efficacy evidence is preclinical — the human anticonvulsant trials are ongoing, and no efficacy results have been published; the short duration of action seen in animals is an open question.

Huperzine A binds acetylcholinesterase reversibly. While it is bound, the enzyme is shielded from the permanent damage caused by organophosphate pesticides and nerve agents, which is why military researchers have studied it as a pretreatment ^{17Reference 17Gordon RK et al. · 2001In vitroThe NMDA receptor ion channel: a site for binding of huperzine A — in vitroView study →}.

In a Phase Ib study, oral huperzine A at 100–400 µg twice daily inhibited red-blood-cell acetylcholinesterase by 30–40% at 100 µg and by more than 50% at 400 µg. When blood samples were exposed to the nerve agent soman outside the body, the enzyme that huperzine A had bound recovered its activity afterwards ^{15Reference 15Haigh JR et al. · 2008Clinical trialProtection of red blood cell acetylcholinesterase by oral huperzine A against ex vivo soman exposure — clinical trial / ex vivoView study →}.

In cynomolgus macaques huperzine A was 88 times more potent than galantamine, showed no behavioural toxicity, and protected against the overt signs of a lethal dose of soman ^{16Reference 16Hamilton LR et al. · 2017AnimalTime course, behavioral safety, and protective efficacy of centrally active reversible acetylcholinesterase inhibitors in cynomolgus macaques — animal in vivoView study →}. It also binds the NMDA receptor channel, which may add protection against nerve-agent seizures ^{17Reference 17Gordon RK et al. · 2001In vitroThe NMDA receptor ion channel: a site for binding of huperzine A — in vitroView study →}.

The human evidence stops at enzyme protection, because protection against real exposure cannot be tested in people.

In a randomised, double-blind trial in 78 patients with mild-to-moderate vascular dementia, huperzine A 0.1 mg twice daily for 12 weeks improved MMSE, clinical dementia rating and daily-living scores, with no serious adverse events ^{18Reference 18Xu ZQ et al. · 2012RCTTreatment with huperzine A improves cognition in vascular dementia patients — randomised controlled trialView study →}.

A meta-analysis that pooled two vascular dementia trials (92 participants) with eight Alzheimer’s trials found benefit in both groups, with possibly fewer side effects in vascular dementia ^{6Reference 6Xing SH et al. · 2014Meta-analysisHuperzine A in the treatment of Alzheimer’s disease and vascular dementia: a meta-analysis — meta-analysisView study →}.

The Cochrane review of huperzine A for vascular dementia included only one small trial of 14 participants. It found no significant effect on MMSE and no convincing evidence of value ^{19Reference 19Hao Z et al. · 2009Systematic reviewHuperzine A for vascular dementia — systematic review (Cochrane)View study →}.

Huperzine A also protects nerve tissue in injury models by routes other than acetylcholinesterase ^{8Reference 8Qian ZM · 2014ReviewHuperzine A: is it an effective disease-modifying drug for Alzheimer’s disease? — reviewView study →}.

In a mouse model of traumatic brain injury it reduced oxidative stress (lower malondialdehyde, higher glutathione peroxidase) by activating the Nrf2-ARE antioxidant pathway ^{21Reference 21Mei Z et al. · 2021AnimalHuperzine A protects against traumatic brain injury through anti-oxidative effects via the Nrf2-ARE pathway — mouse in vivoView study →}.

It reduces oxidative injury from amyloid-beta and raises nerve growth factor. In cell studies it shifts amyloid precursor protein processing away from the amyloid-forming route, lowering BACE1 and raising ADAM10 ^{8,25Reference 8Qian ZM · 2014ReviewHuperzine A: is it an effective disease-modifying drug for Alzheimer’s disease? — reviewView study →Reference 25Wongjaikam S et al. · 2024In vitroHuperzine A regulates the physiological homeostasis of amyloid precursor protein proteolysis and tau protein conformation — in vitro / in silicoView study →}.

It also dampens inflammation, protecting against acute lung injury from lipopolysaccharide and sepsis in mice through the α7-nicotinic receptor and by suppressing ferroptosis ^{23,24Reference 23Su J et al. · 2024AnimalHuperzine A ameliorates sepsis-induced acute lung injury by suppressing inflammation and oxidative stress via α7 nicotinic acetylcholine receptor — mouse in vivoView study →Reference 24Shi J et al. · 2024In vitroHuperzine A protected against ferroptosis via activating PI3K/Akt signaling in lipopolysaccharide-induced acute lung injury — in vivo / in vitroView study →}.

The total alkaloid fraction of the plant, not just the isolated molecule, showed antioxidant and anti-amnesic activity in scopolamine-treated mice ^{22Reference 22Dang TK et al. · 2023AnimalNeuroprotective effects of total alkaloids fraction of Huperzia serrata on scopolamine-induced neurodegenerative animals — mouse in vivoView study →}.

All of these findings are from animals or cell lines.

In an MPTP-induced mouse model of Parkinson’s disease, huperzine A injection improved motor and cognitive deficits and protected dopamine-producing neurons, apparently by modulating inflammatory and other pathways ^{26Reference 26Guo X et al. · 2023AnimalHuperzine A injection ameliorates motor and cognitive abnormalities via regulating multiple pathways in a murine model of Parkinson’s disease — mouse in vivoView study →}.

Related work suggests that acetylcholinesterase levels influence the death of dopamine-producing neurons ^{27Reference 27Zhang X et al. · 2013AnimalAcetylcholinesterase deficiency decreases apoptosis in dopaminergic neurons — animal in vivoView study →}. Only mouse data exist, and no human trial in Parkinson’s disease has been run.

The most-cited human study is a 1999 double-blind trial in 34 matched pairs of junior middle school students who complained of poor memory. Huperzine A at 50 µg twice daily for 4 weeks raised memory quotient and Chinese-language scores compared with placebo ^{28Reference 28Sun QQ et al. · 1999RCTHuperzine-A capsules enhance memory and learning performance in 34 pairs of matched adolescent students — randomised controlled trialView study →}.

An older double-blind trial reported benefit from injected huperzine A in older adults with simple memory disorders ^{29Reference 29Zhang RW et al. · 1991RCTDrug evaluation of huperzine A in the treatment of senile memory disorders — randomised controlled trialView study →}.

In healthy young adults, single doses of 100 or 200 µg inhibited red-blood-cell acetylcholinesterase but did not improve performance on neurobehavioural tests ^{30Reference 30Morasch KC et al. · 2015RCTPhysiological and neurobehavioral effects of cholinesterase inhibition in healthy adults — placebo-controlled human studyView study →}.

Gap: the only supportive trial of oral huperzine A for memory is small, decades old and in adolescents, and there is no adequately powered trial of repeated dosing in healthy adults.

Side effects. The adverse effects of huperzine A are the expected cholinergic ones: nausea and stomach upset, dizziness, sweating and a slower heart rate. In Alzheimer’s trials they were generally mild to moderate and short-lived at 200–400 µg twice daily ^{2,4,6Reference 2Rafii MS et al. · 2011RCTA phase II trial of huperzine A in mild to moderate Alzheimer disease — randomised controlled trialView study →Reference 4Yang G et al. · 2013Meta-analysisHuperzine A for Alzheimer’s disease: a systematic review and meta-analysis of randomised clinical trials — meta-analysisView study →Reference 6Xing SH et al. · 2014Meta-analysisHuperzine A in the treatment of Alzheimer’s disease and vascular dementia: a meta-analysis — meta-analysisView study →}.

Drug interactions. Huperzine A is expected to add to other cholinesterase inhibitors, such as donepezil, rivastigmine and galantamine and the drugs used for glaucoma or myasthenia gravis. Anticholinergic drugs oppose its action. It may add to heart-slowing drugs such as beta-blockers. These interactions are predicted from its action and have not been tested ^{1,8Reference 1Ma X et al. · 2007ReviewHuperzine A from Huperzia species — an ethnopharmacological review — reviewView study →Reference 8Qian ZM · 2014ReviewHuperzine A: is it an effective disease-modifying drug for Alzheimer’s disease? — reviewView study →}.

Conditions to avoid. It should not be used with a slow heart rate or other heart-conduction problems, epilepsy or other seizure disorders, asthma or COPD (acetylcholine narrows the airways), peptic ulcer, or bowel or urinary obstruction ^{1,8Reference 1Ma X et al. · 2007ReviewHuperzine A from Huperzia species — an ethnopharmacological review — reviewView study →Reference 8Qian ZM · 2014ReviewHuperzine A: is it an effective disease-modifying drug for Alzheimer’s disease? — reviewView study →}.

Long-term use and product quality. No long-term human safety studies of huperzine A exist, and the whole plant has no formal safety data ^{1,8Reference 1Ma X et al. · 2007ReviewHuperzine A from Huperzia species — an ethnopharmacological review — reviewView study →Reference 8Qian ZM · 2014ReviewHuperzine A: is it an effective disease-modifying drug for Alzheimer’s disease? — reviewView study →}. Huperzine A is a licensed drug in China but a dietary supplement in the United States, where product content and purity vary widely.