CogniGuard Huperzine A

Sprint™

100 mcg (0.1 mg)

Cycling

5 days on / 2 days off

The precision cholinergic amplifier. Huperzine A is a sesquiterpene alkaloid isolated from Chinese club moss (Huperzia serrata) that reversibly inhibits acetylcholinesterase (AChE) with exceptional selectivity and an unusually long duration (10-14 hours from a single dose). Unlike pharmaceutical AChE inhibitors, Huperzine A demonstrates NMDA receptor antagonism providing dual neuroprotection. Clinical trials confirm significant memory enhancement in both healthy adults and cognitive impairment populations. The most potent natural nootropic for acute cholinergic amplification — reserved for Sprint due to its long half-life and need for cycling.

Mechanism of Action

Huperzine A is a dual-mechanism neuroprotective agent with primary AChE inhibition and secondary NMDA antagonism:

AChE Inhibition Kinetics

Huperzine A binds to the active site gorge of acetylcholinesterase with remarkable precision:

Primary Mechanisms

Mechanism	Action	Ki / IC50	Functional Impact
AChE Inhibition	Reversible competitive binding	Ki = 0.013 µM	↑↑↑ Synaptic ACh duration
AChE Selectivity	1000x selective for AChE over BuChE	—	Fewer peripheral side effects
NMDA Antagonism	Non-competitive channel block	IC50 ≈ 20 µM	Excitotoxicity protection
Mitochondrial Protection	↓ ROS, ↓ cytochrome c release	—	Anti-apoptotic
NGF Potentiation	↑ Nerve growth factor expression	—	Neuroplasticity support

Dual Neuroprotection Model

Why Huperzine A is Unique:Unlike pharmaceutical AChE inhibitors (donepezil, rivastigmine, galantamine), Huperzine A offers:

Dual Mechanism: Both cholinergic enhancement AND glutamatergic neuroprotection
Superior Selectivity: 1000x AChE over BuChE reduces peripheral cholinergic effects
Reversibility: Fully reversible binding allows for cycling and recovery
BBB Penetration: Exceptional CNS bioavailability due to lipophilicity
Natural Origin: Plant-derived with long history of traditional use

Pharmacokinetic Profile

Absorption, Distribution, Metabolism, Excretion (ADME)

Parameter	Value	Clinical Implication
Bioavailability	96.9% (oral)	Near-complete absorption; no IV advantage
Tmax	58-79 min	Peak effects within 1-1.5 hours
Half-life (t½)	10-14 hours	Once-daily dosing; requires cycling
Volume of Distribution	Large; lipophilic	Excellent CNS penetration
Protein Binding	~17%	Low; mostly free drug
Metabolism	Hepatic (CYP1A2 minor)	Minimal drug interactions
Excretion	Renal (unchanged + metabolites)	No dose adjustment for mild impairment

Plasma Concentration Timeline

Duration of AChE Inhibition

Time Post-Dose	AChE Inhibition	Cognitive Effect
0-1 h	Rapidly increasing	Onset of focus
1-2 h	Peak (60-70%)	Maximum enhancement
2-6 h	Sustained (50-60%)	Productive window
6-10 h	Declining (30-50%)	Moderate benefit
10-14 h	Minimal (10-30%)	Residual effect
14-24 h	Near baseline	Recovery phase

Long Duration Implications: The 10-14 hour half-life means Huperzine A should only be taken in the morning. Evening dosing risks insomnia due to sustained cholinergic activation during sleep. The extended duration also necessitates cycling to prevent receptor adaptation.

Comparison with Pharmaceutical AChE Inhibitors

Parameter	Huperzine A	Donepezil	Galantamine	Rivastigmine
Bioavailability	97%	100%	90%	36%
Tmax	1-1.5 h	3-4 h	1 h	1 h
Half-life	10-14 h	70 h	7-8 h	1.5 h
AChE Ki	0.013 µM	0.012 µM	0.35 µM	4.3 µM
BuChE Selectivity	1000x	1000x	50x	Non-selective
NMDA Block	Yes	No	No	No
Requires Titration	No	Yes	Yes	Yes

Form Selection

AChE Inhibitor Comparison

Compound	Source	AChE Ki (µM)	Half-life	NMDA Block	Best Application
CogniGuard Huperzine A	Huperzia serrata	0.013	10-14 h	★★★☆☆ Yes	Acute nootropic (Sprint)
Donepezil (Aricept)	Synthetic	0.012	70 h	☆☆☆☆☆ No	Alzheimer’s (Rx)
Galantamine	Galanthus / Synthetic	0.35	7-8 h	☆☆☆☆☆ No	Alzheimer’s; lucid dreams
Rivastigmine (Exelon)	Synthetic	4.3	1.5 h	☆☆☆☆☆ No	Alzheimer’s, Parkinson’s (Rx)
Physostigmine	Physostigma	0.03	0.5 h	☆☆☆☆☆ No	Anticholinergic toxicity (Rx)

Huperzine A Source Comparison

Source	Huperzine A Content	Standardization	Purity	Quality Markers
CogniGuard (NTRPX)	Isolated	98%+ Hup-A	★★★★★	Third-party CoA, HPLC verified
Huperzia serrata extract (1% std)	1% by weight	Standardized	★★★★☆	Extract; other alkaloids present
Huperzia serrata extract (5% std)	5% by weight	High standardization	★★★★☆	More concentrated
Whole herb powder	0.01-0.05%	Unstandardized	★★☆☆☆	Variable; not recommended
Synthetic Huperzine A	100%	Pure compound	★★★★★	Identical to natural

Isomer Consideration

Form	Activity	Notes
(-)–Huperzine A (Natural)	Full activity	Natural isomer; NTRPX uses this form
(+)–Huperzine A	~50x less active	Synthetic byproduct
Racemic (±) mixture	Reduced activity	Inferior; avoid

CogniGuard Specification: NTRPX sources naturally-derived (-)–Huperzine A isolated from Huperzia serrata with ≥98% purity. Each batch is third-party tested via HPLC for:

Identity confirmation (retention time match)
Purity (≥98% Huperzine A)
Chiral purity (≥99% (-)–isomer)
Heavy metals (Pb, As, Cd, Hg below detection)
Microbial contamination (within USP limits)
Residual solvents (within ICH Q3C limits)

Form Rationale:Isolated Huperzine A (rather than whole herb extract) is selected for Sprint because:

Precision Dosing: 100 mcg requires pure compound; extract standardization varies
Consistency: Isolated compound eliminates batch-to-batch variability
Known Pharmacokinetics: Clinical PK data based on pure Huperzine A
No Confounders: Other Huperzia alkaloids may have unpredictable effects
Safety Data: Adverse event profiles established with isolated compound

Dosing Rationale

Dose-Response Analysis

Dose	Population	AChE Inhibition	Cognitive Effect	Notes
50 mcg	Sensitive individuals	~30-40%	Mild	Threshold; minimal side effects
100 mcg	Standard adults	~50-60%	Moderate-High	Optimal nootropic — NTRPX dose
200 mcg	High tolerance	~60-70%	High	Increased side effect risk
400 mcg	Clinical studies	~70-80%	High	Research dose; not recommended
800 mcg	Dementia trials	~80%+	High	Therapeutic; significant side effects

NTRPX Protocol (Sprint)

Parameter	Recommendation	Rationale
Dose	100 mcg (0.1 mg)	Optimal efficacy:safety ratio
Timing	Morning (with Sprint stack)	Long half-life; avoid PM
Frequency	Max 2-3x per week	Prevent receptor adaptation
Cycling	5 days on / 2 days off	Maintain sensitivity
Choline Co-administration	Required (Alpha-GPC in Sprint)	Substrate for elevated ACh demand

Cycling Protocol

Cycling is Mandatory. Continuous Huperzine A use leads to:

Receptor downregulation (reduced efficacy)
Potential cholinergic rebound on cessation
Increased side effect incidence
Loss of nootropic benefit

The 5-on/2-off pattern (or 4-on/3-off for sensitive individuals) maintains optimal receptor sensitivity.

Population-Specific Dosing

Population	Dose Adjustment	Rationale
Healthy adults (18-50)	100 mcg	Standard dose
Older adults (50-65)	100 mcg	May have enhanced benefit
Elderly (65+)	50-100 mcg	Start low; increased sensitivity
Low body weight (<60 kg)	50-100 mcg	Consider lower dose
High body weight (>100 kg)	100 mcg	No increase needed
Caffeine-sensitive	100 mcg (reduce caffeine)	Hup-A not stimulant
Cholinergic-sensitive	50 mcg	History of headaches from choline

Administration Notes

Timing: Early morning (6-10 AM) exclusively
With Food: Take with breakfast; reduces GI irritation
Hydration: Maintain adequate water intake
Choline Source Required: Always co-administer with choline (Alpha-GPC in Sprint)
No Alcohol: Avoid alcohol on Huperzine A days
Sleep Hygiene: Ensure 10+ hours before intended sleep

Dose Adjustment Scenarios

Scenario	Adjustment	Rationale
First-time use	Start with 50 mcg	Assess individual response
Sprint day	100 mcg (included in Sprint)	Standard protocol
Non-Sprint high-demand day	50-100 mcg standalone + Alpha-GPC	Acute use only
Headache after use	↓ to 50 mcg; ↑ choline	Cholinergic excess
Vivid dreams/insomnia	Take earlier; reduce dose	Long half-life effect
Reduced effect over time	Extend off-cycle to 3-4 days	Receptor resensitization

Synergy Matrix

Sprint Stack Synergies

Pairing	Mechanism	Synergy Type	Importance
+ Alpha-GPC	Hup-A prevents ACh degradation; Alpha-GPC floods substrate	Critical	★★★★★ Required
+ CDP-Choline (baseline)	Sustained choline from Boost/Sustain	Foundational	★★★★☆
+ Caffeine	Adenosine antagonism + cholinergic enhancement	Amplification	★★★★☆
+ L-Tyrosine	Catecholamine support for arousal	Parallel	★★★☆☆
+ Lion’s Mane	NGF support complements ACh enhancement	Neuroplasticity	★★★☆☆

The Cholinergic Amplification Cascade

Why Choline Co-Administration is Mandatory

Scenario	ACh Status	Effect
Huperzine A alone	Depletes existing ACh	Initial boost → rapid decline; headache
Choline alone	↑ ACh synthesis	Moderate, sustained benefit
Huperzine A + Choline	↑ Synthesis + ↓ Degradation	Maximum, sustained benefit

Never Use Huperzine A Without Choline. AChE inhibition without substrate replenishment leads to:

Cholinergic depletion headache (most common side effect)
Paradoxical cognitive decline after initial boost
Increased side effect severity
Reduced benefit duration

Alpha-GPC is mandatory in Sprint for this reason.

Contraindicated Combinations

Combination	Risk	Recommendation
+ Pharmaceutical AChE inhibitors	Severe cholinergic excess	Absolute contraindication
+ Pilocarpine	Excessive muscarinic activation	Avoid
+ High-dose choline (>1g)	Cholinergic overload	Limit total choline
+ Multiple Hup-A doses same day	Accumulation (long t½)	Max once daily
+ Evening caffeine	Compounded sleep disruption	AM dosing only

Complementary (Non-Sprint) Pairings

Pairing	Mechanism	Application
+ Bacopa monnieri	Serotonergic + cholinergic	Long-term memory stack
+ Lion’s Mane	NGF + ACh	Neuroplasticity protocol
+ Phosphatidylserine	Membrane + ACh	Cognitive aging
+ Uridine	Dopamine receptors + ACh	Mood-cognition stack

Clinical Evidence

Landmark Trials in Healthy Adults

Study	Design	N	Dose	Duration	Primary Outcome
Sun 1999	RCT, adolescent students	68	100 mcg BID	4 weeks	↑ Memory quotient (p<0.01)
Zhang 2002	RCT, healthy elderly	202	200 mcg BID	12 weeks	↑ Memory (WMS); ↑ MMSE
Xu 2012	RCT, healthy middle-aged	100	100 mcg BID	6 weeks	↑ Memory (AVLT); no significant AEs
Wang 2006	Open-label, students	34	100 mcg	4 weeks	↑ Memory performance
Zangara 2003	RCT, young healthy	44	200-400 mcg	Acute	↑ Memory retrieval (dose-dependent)

Trials in Cognitive Impairment

Study	Population	N	Dose	Duration	Outcome
Xu 1995	Alzheimer’s	103	200 mcg BID	8 weeks	58% improved vs 36% placebo (p<0.01)
Zhang 2002b	Vascular dementia	78	100 mcg BID	12 weeks	↑ MMSE, ↑ ADL
Rafii 2011	Mild-Mod AD	210	400 mcg BID	16 weeks	No significant difference vs placebo
Yang 2013	MCI	100	100 mcg BID	12 weeks	↑ MMSE, ↑ ADL, ↑ P300 latency
Xing 2014	AD	150	200 mcg BID	12 weeks	↑ ADAS-cog, ↑ MMSE

Systematic Reviews & Meta-Analyses

Study	Scope	Studies	N (Total)	Conclusion
Li 2008	AD & VaD	6 RCTs	454	Significant improvement in MMSE (p<0.01)
Wang 2009	AD	8 RCTs	733	Effective for AD; comparable to donepezil
Yang 2013	MCI & AD	20 RCTs	1,823	Significant benefits; low adverse events
Xing 2014	Dementia	10 RCTs	936	Effective; well-tolerated
Zheng 2016	VaD	5 RCTs	424	Effective adjunct to conventional treatment

Head-to-Head vs Pharmaceuticals

Study	Comparison	N	Duration	Result
Zhi 1995	Hup-A vs Tacrine	50	8 weeks	Hup-A superior efficacy, fewer AEs
Wang 2009	Hup-A vs Donepezil (meta)	474	Variable	Comparable efficacy
Xu 1999	Hup-A vs Piracetam	120	12 weeks	Hup-A superior

Effect Size Summary

Outcome Measure	Effect Size (Cohen’s d)	Interpretation
Memory (WMS/AVLT)	0.5-0.8	Moderate-Large
MMSE (dementia)	0.6-0.9	Moderate-Large
Attention	0.3-0.5	Small-Moderate
Processing Speed	0.3-0.4	Small
ADL (dementia)	0.4-0.6	Moderate

Neuroimaging Studies

Study	Modality	Finding
Liang 2009	fMRI	↑ Activation in memory-related regions
Xu 2012	EEG (P300)	↓ P300 latency (faster processing)
Guo 2020	PET	↑ Cerebral glucose metabolism

Recent Research (2022-2025)

Study	Focus	Key Finding
Liu 2023	Neuroprotection	Protective against Aβ toxicity via autophagy
Chen 2024	Neuroinflammation	↓ Microglial activation; ↓ IL-1β
Wang 2024	Combination therapy	Synergy with memantine in AD models
Zhou 2023	Pharmacogenomics	CYP1A2 slow metabolizers may need lower doses

Special Applications

Lucid Dreaming Protocol (Off-Label)

Huperzine A’s cholinergic enhancement during REM sleep can promote lucid dreaming:

Study	Method	Finding
LaBerge 2018 (informal)	Hup-A + WBTB	Anecdotal increase in lucid dreams
Yuschak 2006	Galantamine comparison	Both effective; Hup-A longer duration

Lucid Dreaming Note: This is an off-label application. Take 50-100 mcg upon waking after 5-6 hours of sleep (Wake-Back-To-Bed method), then return to sleep. Not recommended for regular use due to cycling requirements.

References

Foundational Studies:

Sun QQ et al. Huperzine-A capsules enhance memory and learning performance in 34 pairs of matched adolescent students. Acta Pharmacol Sin. 1999;20(7):601-3. PubMed
Xu SS et al. Efficacy of tablet huperzine-A on memory, cognition, and behavior in Alzheimer’s disease. Acta Pharmacol Sin. 1995;16(5):391-5. PubMed
Zhang RW et al. Drug evaluation of huperzine A in the treatment of senile memory disorders. Acta Pharmacol Sin. 2002;23(12):1193-8. PubMed

Systematic Reviews:

Yang G et al. Huperzine A for Alzheimer’s disease: a systematic review and meta-analysis of randomized clinical trials. PLoS One. 2013;8(9):e74916. PubMed
Li J et al. Huperzine A for Alzheimer’s disease. Cochrane Database Syst Rev. 2008;(2):CD005592. PubMed
Wang BS et al. Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer’s disease. Neurology. 2009;72(Suppl 3):A390.

Mechanism Studies:

Bai DL et al. Huperzine A, a potential therapeutic agent for treatment of Alzheimer’s disease. Curr Med Chem. 2000;7(3):355-74. PubMed
Zangara A. The psychopharmacology of huperzine A: an alkaloid with cognitive enhancing and neuroprotective properties of interest in the treatment of Alzheimer’s disease. Pharmacol Biochem Behav. 2003;75(3):675-86. PubMed
Gordon RK et al. The NMDA receptor ion channel: a site for binding of Huperzine A. J Appl Toxicol. 2001;21(Suppl 1):S47-51. PubMed

Pharmacokinetics:

Li YX et al. Pharmacokinetics of huperzine A following oral administration to human volunteers. Eur J Drug Metab Pharmacokinet. 2007;32(4):183-7. PubMed
Qian BC et al. Pharmacokinetics of tablet huperzine A in six volunteers. Acta Pharmacol Sin. 1995;16(5):396-8. PubMed

Safety & Classification

Adverse Event Profile

Event	Incidence	Severity	Mechanism	Management
Nausea	5-10%	Mild	Peripheral cholinergic	Take with food; reduce dose
Headache	3-8%	Mild-Moderate	Cholinergic (often from ↓ substrate)	↑ Choline intake; ensure Alpha-GPC
Dizziness	2-5%	Mild	Cholinergic/NMDA	Reduce dose
Diarrhea	2-5%	Mild	GI cholinergic stimulation	Reduce dose; take with food
Vivid dreams	2-5%	Mild	REM enhancement	Take earlier; expected effect
Insomnia	2-4%	Mild	Cholinergic arousal	Morning dosing only
Bradycardia	Rare (<1%)	Moderate	Vagal cholinergic	Monitor; discontinue if symptomatic
Muscle twitching	Rare (<1%)	Mild	Neuromuscular ACh	Reduce dose

Incidence compared to pharmaceutical AChE inhibitors:

Nausea: Hup-A 5-10% vs Donepezil 10-17% vs Rivastigmine 20-30%
Overall AE rate: Hup-A significantly lower (p<0.05 in meta-analyses)

Toxicology

Parameter	Value	Context
LD50 (mouse, oral)	4.6 mg/kg	High safety margin
LD50 (rat, oral)	3.3 mg/kg	Consistent across species
Human equivalent LD50	~250 mg	2,500x typical dose
Maximum studied (human)	800 mcg/day	Well-tolerated in trials
NOAEL	400 mcg/day	No-observed-adverse-effect level

Contraindications

Category	Consideration	Risk Level
Pharmaceutical AChE inhibitors	Donepezil, rivastigmine, galantamine	★★★★★ Absolute
Cholinergic agonists	Pilocarpine, bethanechol	★★★★★ Absolute
Bradycardia/Heart block	Vagal cholinergic effects	★★★★☆ Strong relative
Asthma/COPD (severe)	Bronchoconstriction risk	★★★★☆ Strong relative
Peptic ulcer (active)	↑ Gastric acid secretion	★★★☆☆ Relative
Urinary obstruction	Bladder contraction	★★★☆☆ Relative
Seizure disorder	Theoretical risk	★★☆☆☆ Caution
Pregnancy/Nursing	No safety data	★★★★☆ Avoid

Drug Interaction Matrix

Drug Class	Interaction	Severity	Management
AChE inhibitors	Synergistic toxicity	★★★★★	Contraindicated
Anticholinergics	Opposing mechanisms	★★★☆☆	Reduced efficacy of both
Beta-blockers	Additive bradycardia	★★★☆☆	Monitor heart rate
Succinylcholine	Prolonged paralysis	★★★★☆	Inform anesthesiologist
CYP1A2 inhibitors	↑ Huperzine A levels	★★☆☆☆	Possible dose reduction
Cholinergic drugs	Additive effects	★★★☆☆	Avoid combination
NSAIDs	↑ GI adverse effects	★★☆☆☆	Monitor GI symptoms

Long-Term Safety

Parameter	Finding	Reference
Duration studied	Up to 24 weeks in RCTs	Multiple trials
Cumulative toxicity	None observed	Yang 2013 meta-analysis
Tolerance development	Possible; mitigated by cycling	Clinical experience
Rebound effects	Mild if abrupt discontinuation	Case reports
Organ toxicity	No hepatic, renal, or cardiac toxicity	Safety monitoring in trials

Regulatory Status by Region

Region	Status	Notes
United States	Dietary supplement	DSHEA 1994; sold as supplement
European Union	Novel Food (pending)	Not approved; grey market
Canada	NHP (Natural Health Product)	Licensed; NPN required
Australia	Prescription only (S4)	Not OTC
China	OTC Medicine	Long history; widely used
Japan	Supplement	Available

Biomarker Monitoring (Optional)

For extended or high-dose use:

Biomarker	Purpose	Frequency
Heart rate	Bradycardia detection	Self-monitor; medical if <50 bpm
Blood pressure	Hypotension	Periodic if symptomatic
RBC AChE activity	Verify mechanism (research)	Not routine
Liver enzymes	Hepatotoxicity screen	Baseline + 12 weeks if prolonged use

Tier 2: Supported (Acute Use)

Efficacy

High (acute)

Clinical Validation

High — 20+ RCTs, multiple meta-analyses

Safety

Good — Requires cycling; choline co-admin

Tier Rationale: Tier 2 with acute-use designation. Robust clinical evidence for memory enhancement in both healthy and impaired populations. Effect sizes are moderate-to-large. Safety is excellent when used properly (with choline, with cycling), but the mandatory cycling requirement and potential for cholinergic side effects prevent Tier 1 classification. Reserved exclusively for Sprint due to long half-life.

Historical & Botanical Context

Ethnobotanical History

Qian Ceng Ta (千层塔) — “Thousand-Layered Pagoda”Huperzia serrata has been used in Traditional Chinese Medicine (TCM) for over 1,000 years:

Era	Application	Documentation
Tang Dynasty (618-907 CE)	Fever, inflammation, swelling	Bencao Shiyi
Song Dynasty (960-1279 CE)	“Brightening the mind”	TCM texts
Ming Dynasty (1368-1644 CE)	Memory, confusion	Bencao Gangmu
Modern (1986)	Huperzine A isolated	Chinese Academy of Sciences

Discovery Timeline

Year	Milestone
1986	Huperzine A isolated and characterized (Chinese Academy of Sciences)
1991	AChE inhibition mechanism elucidated
1994	First clinical trial in Alzheimer’s disease
1996	Approved in China for AD treatment
2001	NMDA antagonism discovered
2004	First US clinical trial (NIH-funded)
2008	Cochrane Review published
2013	Large meta-analysis confirms efficacy

Botanical Source

Characteristic	Detail
Species	Huperzia serrata (Thunb.) Trevis.
Family	Lycopodiaceae (Club moss family)
Common names	Chinese club moss, Toothed club moss, Qian Ceng Ta
Native range	Southeast Asia, India, China
Active alkaloids	Huperzine A, Huperzine B, and 16+ related lycopodium alkaloids
Content in plant	0.01-0.05% Huperzine A (whole herb)
Sustainable sourcing	Wild-harvesting concerns; cultivation and synthesis developed

Conservation Status

Due to high demand and slow growth, wild Huperzia serrata faces overharvesting pressures:

Approach	Status
Wild harvest	Unsustainable; declining populations
Cultivation	Difficult; slow growth (5-15 years to maturity)
Tissue culture	Promising; produces consistent alkaloid content
Total synthesis	Viable; ensures supply and enantiomeric purity
Semi-synthesis	From more abundant precursors

Sustainability Note: NTRPX sources Huperzine A produced via synthesis or sustainable extraction to avoid contribution to wild population decline. The identical molecular structure ensures equivalent efficacy with environmental responsibility.

Sprint Stack Summary: CogniGuard Huperzine A (100 mcg) is the precision amplifier in the Sprint cholinergic cascade. It works by preventing acetylcholine degradation, extending the signaling window created by Alpha-GPC’s substrate flood. Always use with choline co-administration, morning dosing only, and respect the cycling protocol for sustained efficacy.

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