Meta Information
ID:huperzine-a
Name:
Schema Version:2.4_uniform_evidence_2026_06_18
Created
2026-05-21T22:30:00Z
Model
phase-a-upgrade-claude-sonnet-4.6
Interactions
Target id:
/class/cholinesterase-inhibitors
Target name:
Other Cholinesterase Inhibitors (e.g., Donepezil, Rivastigmine)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Combining two drugs that inhibit the same enzyme (acetylcholinesterase) leads to an excessive buildup of acetylcholine, causing a high risk of severe side effects known as cholinergic crisis.
Actionable advice:
Huperzine A should not be taken with any prescription cholinesterase inhibitor.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
(--)-Huperzine A and donepezil caused mortality and significant toxicity in the BChE-/- animals.
Label source:
PubMed: Toxicology (2007)
Source url:
Exact phrase from label:
Our results showed that huperzine A (0.25, 0.5, and 0.75 micromol/kg, po) dose-dependently elevated extracellular acetylcholine (ACh) levels in the medial prefrontal cortex (mPFC) and hippocampus. Oral administration of donepezil (5.4 micromol/kg) or rivastigmine (1 micromol/kg) also elicited significant increases in ACh in the mPFC and hippocampus.
Label source:
PubMed: Acta pharmacologica Sinica (2006)
Source url:
Exact phrase from label:
Five inhibitors of acetylcholinesterase, huperzine A, donepezil, tacrine, rivastigmine and physostigmine, were compared with regard to their effects on different molecular forms of acetylcholinesterase in cerebral cortex, hippocampus, and striatum from the rat brain.
Label source:
PubMed: European journal of pharmacology (2002)
Action type:
avoid
Target id:
/intervention/galanthamine
Target name:
Galanthamine
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Both Huperzine A and Galanthamine are potent acetylcholinesterase inhibitors; taking them together creates a high risk of cholinergic crisis (severe nausea, bradycardia, muscle weakness).
Actionable advice:
Huperzine A and Galanthamine should not be taken together.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Exact phrase from label:
A synergistic effect is expected when cholinesterase inhibitors are given concurrently with succinylcholine, other cholinesterase inhibitors, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol
Label source:
FDA label: Galantamine (Razadyne ER)
Action type:
avoid
Target id:
/class/anticholinergic-medications
Target name:
Anticholinergic Medications (e.g., Diphenhydramine, Scopolamine)
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Huperzine A increases acetylcholine levels, while anticholinergic drugs block its effects, leading to opposing actions that can reduce the efficacy of both and cause unpredictable side effects.
Actionable advice:
Huperzine A is best avoided with anticholinergic medications, as they counteract each other.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
The effects of (-)-huperzine A ((5R,9R,11E)-5-amino-11-ethylidene-5,6,9,10-tetrahydro-7-methyl-5, 9-methanocycloocta[b]pyridin-2(1H)-one), and of the hydrochloride salt of E2020 ((R,S)-1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methyl piperidine) and tacrine (9-amino-1,2,3,4-tetrahydroacridine), on the scopolamine-induced memory deficits in rats were compared in a radial maze, using a 4-out-of-8 baiting procedure.
Label source:
PubMed: Reversal of scopolamine-induced deficits in radial maze performance by (-)-huperzine A: comparison with E2020 and tacrine. (PMID 9671090)
Action type:
avoid
Target id:
/class/cholinergic-agonists
Target name:
Cholinergic Agonists (e.g., Bethanechol, Pilocarpine)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Combining a drug that prevents acetylcholine breakdown (Huperzine A) with one that directly stimulates acetylcholine receptors leads to excessive cholinergic activity and a high risk of severe side effects.
Actionable advice:
Huperzine A should not be taken with any cholinergic agonist medication.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Exact phrase from label:
A synergistic effect is expected when cholinesterase inhibitors are given concurrently with succinylcholine, other cholinesterase inhibitors, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol
Label source:
FDA label: Galantamine (Razadyne ER) [class-derived from: galantamine]
Action type:
avoid
Target id:
/procedure/surgery-anesthesia
Target name:
Surgery with Anesthesia
Severity:
major
Interaction type:
adverse
Nature:
temporal
Temporal spacing:
Hours before target:
72
Hours after target:
null
Description:
Huperzine A can prolong the effects of certain neuromuscular blocking agents used in anesthesia (like succinylcholine), potentially leading to delayed recovery and respiratory complications.
Actionable advice:
Huperzine A should be discontinued at least 3-5 days before any scheduled surgery.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Exact phrase from label:
Galantamine, as a cholinesterase inhibitor, is likely to exaggerate the neuromuscular blocking effects of succinylcholine-type and similar neuromuscular blocking agents during anesthesia.
Label source:
FDA label: Galantamine (Razadyne ER) [class-derived from: galantamine]
Action type:
avoid
Target id:
/class/beta-blockers
Target name:
Beta-Blockers
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Both Huperzine A (by increasing vagal tone) and beta-blockers can slow the heart rate (bradycardia); their combined use increases the risk of an excessive drop in heart rate.
Actionable advice:
It is important to consult a doctor before combining; it is a good idea to monitor heart rate closely if approved.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
beta-blockers can increase the risk of bradycardia.
Label source:
Action type:
monitor
Target id:
/intervention/digoxin
Target name:
Digoxin
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Both Huperzine A (via cholinergic effects) and Digoxin slow electrical conduction in the heart, increasing the risk of significant bradycardia or heart block when used together.
Actionable advice:
This combination is best avoided unless specifically approved and monitored by a cardiologist.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Bradycardia and heart block caused by digoxin are
parasympathetically mediated and respond to atropine.
Label source:
Action type:
avoid
Target id:
/class/nsaids
Target name:
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Huperzine A may increase stomach acid secretion, which can compound the risk of gastrointestinal bleeding and ulcers associated with NSAID use.
Actionable advice:
Caution is warranted when combining with NSAIDs, especially with long-term use or a history of ulcers.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Gastrointestinal Bleeding, Ulceration, and Perforation
• NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events
including bleeding, ulceration, and perforation of the stomach or intestines, which can
be fatal.
Label source:
Action type:
informational_none
Target id:
/class/choline-precursors
Target name:
Choline Precursors (e.g., Alpha-GPC, Citicoline)
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Choline precursors provide the building blocks for acetylcholine, while Huperzine A prevents its breakdown; this combination can enhance cognitive effects but also increases the risk of cholinergic side effects (headache, nausea).
Actionable advice:
If combining, start with low doses of both and monitor for side effects.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
There are current studies with mixed results regarding the benefit of carnitine, gingko biloba, Huperzine A, vitamin D, and vitamin E supplementation for memory.
Label source:
PubMed: CNS drugs (2023)
Source url:
Exact phrase from label:
The outcomes showed that Huperzine A displayed AChE inhibition, ChAT activity enhancement, memory improvement, and Aβ decreasing activity, indicating the disease-modifying effect of Huperzine A.
Label source:
PubMed: International journal of molecular sciences (2022)
Source url:
Exact phrase from label:
Huperzine A is a linearly competitive, reversible inhibitor of acetyl cholinesterase that is said to have both central and peripheral activity with the ability to protect cells against hydrogen peroxide, beta-amyloid protein (or peptide), glutamate, ischemia and staurosporine-induced cytotoxicity and apoptosis.
Label source:
PubMed: The Cochrane database of systematic reviews (2008)
Action type:
monitor
Target id:
/intervention/dextromethorphan
Target name:
Dextromethorphan (Cough Suppressant)
Severity:
minor
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Both Huperzine A and Dextromethorphan have weak NMDA receptor antagonist properties; combining them could theoretically lead to additive CNS side effects like dizziness or confusion.
Actionable advice:
This is best used with caution, keeping in mind the potential for increased dizziness.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Dextromethorphan is an uncompetitive antagonist of the NMDA receptor (an ionotropic glutamate receptor) and a
sigma-1 receptor agonist.
Label source:
Action type:
informational_none
Target id:
/condition/bradycardia-heart-block
Target name:
Bradycardia or Cardiac Conduction Issues
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Huperzine A increases vagal tone, which slows the heart rate. In individuals with pre-existing bradycardia or heart block, this can lead to dangerously low heart rates or syncope.
Actionable advice:
This should not be used with a slow heart rate or any cardiac conduction abnormalities.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Exact phrase from label:
Because of their pharmacological action, cholinesterase inhibitors have vagotonic effects on the sinoatrial and atrioventricular nodes, leading to bradycardia and AV block.
Label source:
FDA label: Galantamine (Razadyne ER) [class-derived from: galantamine]
Action type:
avoid
Target id:
/condition/peptic-ulcer-disease
Target name:
Peptic Ulcer Disease (PUD)
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Cholinergic stimulation increases the secretion of stomach acid, which can aggravate existing peptic ulcers or increase the risk of their formation.
Actionable advice:
Use is best avoided with an active or recent history of peptic ulcer disease.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
These results suggest that under cholinergic stimulation the acid secretion is directly mediated by M3 receptors and indirectly modified by M4 receptors.
Label source:
PubMed: Activation of Muscarinic Acetylcholine Receptor Subtype 4 Is Essential for Cholinergic Stimulation of Gastric Acid Secretion: Relation to D Cell/Somatostatin. (PMID 27625606)
Action type:
avoid
Target id:
/condition/asthma-copd
Target name:
Asthma and COPD
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Increased acetylcholine levels can cause constriction of the airways (bronchoconstriction), which may trigger or worsen symptoms of asthma or COPD.
Actionable advice:
Use is best avoided with asthma or COPD.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
In the airways, increases in cholinergic nerve activity and cholinergic hypersensitivity are associated with chronic obstructive pulmonary disease and asthma.
Label source:
PubMed: Role of muscarinic receptor subtypes in the constriction of peripheral airways: studies on receptor-deficient mice. (PMID 14645675)
Action type:
avoid
Target id:
/condition/urinary-retention
Target name:
Urinary Retention / BPH or GI Obstruction
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
By increasing cholinergic activity, Huperzine A can increase smooth muscle contractions in the urinary and GI tracts, potentially worsening symptoms of an obstruction.
Actionable advice:
Use is best avoided with a history of urinary or gastrointestinal obstruction.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Exact phrase from label:
Although this was not observed in clinical trials with galantamine, cholinomimetics may cause bladder outflow obstruction.
Label source:
FDA label: Galantamine (Razadyne ER) [class-derived from: galantamine]
Action type:
avoid
Target id:
/condition/pregnancy
Target name:
Pregnancy
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
The safety of Huperzine A during pregnancy has not been established, and its effects on uterine contractions and fetal development are unknown.
Actionable advice:
This should be strictly avoided during pregnancy.
Validation status:
anecdotal
Evidence tier:
tier_d
Evidence basis:
anecdotal_summary
Evidence anchors:
Exact phrase from label:
It is not known if or how huperzine A could affect pregnancy or harm a fetus.
Label source:
Anecdotal: WebMD
Action type:
avoid
Target id:
/condition/lactation
Target name:
Breastfeeding (Lactation)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
It is not known if Huperzine A passes into breast milk or what effects it might have on a nursing infant; therefore, its use is not recommended.
Actionable advice:
It should be avoided completely while breastfeeding.
Validation status:
anecdotal
Evidence tier:
tier_d
Evidence basis:
anecdotal_summary
Evidence anchors:
Exact phrase from label:
There is not enough reliable information about the safety of taking huperzine A if you are pregnant or breast-feeding. Stay on the safe side and avoid use.
Label source:
Anecdotal: RxList
Action type:
avoid
Target id:
/circadian/sleep
Target name:
Going to Sleep
Severity:
minor
Interaction type:
adverse
Nature:
temporal
Temporal spacing:
Hours before target:
6
Hours after target:
null
Description:
As a cognitive stimulant that increases acetylcholine, Huperzine A may interfere with sleep onset or quality for some individuals if taken too close to bedtime.
Actionable advice:
A dose is generally best taken in the morning or early afternoon to avoid potential sleep disturbances.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Primary mechanisms of action include modifications in neurotransmitter synthesis, inhibition of neurotransmitter reuptake and enzyme-induced neurotransmitter breakdown, antioxidant and anti-platelet activity, enhanced blood flow and glucose metabolism.
Label source:
PubMed: Drugs & aging (2003)
Source url:
Exact phrase from label:
Alternative medicines may ameliorate disturbances in cognition, mood, sleep and activities of daily living.
Label source:
PubMed: Drugs & aging (2003)
Action type:
avoid
Target id:
/dietary/meal
Target name:
Any Caloric Meal
Severity:
minor
Interaction type:
informational
Nature:
temporal
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Taking Huperzine A with food may help minimize potential gastrointestinal side effects such as nausea, which can be caused by its cholinergic activity.
Actionable advice:
It is generally best taken with a meal if any stomach upset occurs.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
The acetylcholinesterase inhibitor (AChEI), huperzine A has been used in the treatment of the cognitive deterioration associated with Alzheimer's disease (AD). However, the side-effects of huperzine A associated with increased cholinergic activity, particularly in the gastrointestinal system, are evident.
Label source:
PubMed: Experimental and therapeutic medicine (2013)
Source url:
Exact phrase from label:
However, direct oral administration and injection of HupA cause side effects like nausea, anorexia, and rapid metabolism.
Label source:
PubMed: International journal of biological macromolecules (2024)
Source url:
Exact phrase from label:
However, AChEIs can cause gastrointestinal side effects, which has been related to the high Cmax and short tmax after oral administration.
Label source:
PubMed: Pakistan journal of pharmaceutical sciences (2013)
Action type:
informational_none