Dear Beautiful Self-aware Brain,
In the previous edition of the Structural Brain Health series we explored the top five recommended cognitive enhancement supplements among the top ten most frequently recommended across the top fourteen web (7) and youtube (7) sources.
To re-cap, they include both “direct” and “indirect” cognitive enhancement supplements, ordered by recommendation frequency:
Direct Cognitive Enhancers
Alpha-GPC
Phosphatidylserine
Ginkgo biloba
Caffeine (a stimulant, not a nutrient isolate, included only for synergy with next supplement)
L-Theanine
Bacopa monnieri
Huperzine A
Indirect Cognitive Enhancers
Ashwagandha
Ginseng
Acetyl-L-carnitine
Rhodiola rosea
In recommended doses one could, in theory, take all of the above every day without harm. But no research basis justifies it. And I don’t think anyone should.
So should we take only the top five? Not necessarily. The latter five (6-10) have their places too. Let’s find out what they are.
Every supplement listed above deserves a deep-dive of its own, to help us understand why they’re recommended by the top web and YouTube sources, to decide for ourselves which to take. And they’ll all get one. But for today, Huperzine A is unique among them, and deserves to be first.
Huperzine A
Huperzine A is an alkaloid extract from Huperziaceae plants. Huperzia Serrata plant shown.
There are a few things that separate Huperzine A apart from the others listed here. But the most important one is risk.
We normally think of a supplement as adding (supplementing) a nutrient. Because that’s usually true. Whether it’s something the body can make or not, we consume it for the benefits a higher dose than whole foods alone can provide. Huperzine A is not one of those supplements.
Though not classified as a drug, its mechanism is more like that of a drug than all of the other supplements listed here. It’s the only one of our top ten that can cause whole-body cholinergic toxicity, if dosage is not carefully controlled.1
Mechanism Is The Difference
Huperzine A inhibits acetylcholinesterase (AChE), the enzyme that breaks down the neurotransmitter acetylcholine, by binding to AChE activity sites in the brain.
The neurotransmitter acetylcholine is increased by inhibiting breakdown in active synaptic sites.
And this mechanism can (however unlikely) increase some serious risks. If over-dosed, it can cause2
Abnormally slow heart rate (bradycardia)
Severe breathing difficulties, possible respiratory failure
Seizures
Loss of consciousness 😲
Think about it. No other supplement in this list has this potential.
Only Alpha-CPC, a form of choline (citicoline), comes close. But unlike Huperzine A, Alpha-GPC leaves cellular regulation alone. Whereas Huperzine A’s inhibitory mechanism partially overrides it.
Over-dosing Alpha-GPC can also produce negative effects from cholinergic toxicity:3
Headaches
Nausea
Muscle tension
Sleep disruption
Irritability
The point here is, potential seizures or loss of consciousness are not listed because over-dosing Alpha-GPC can’t disrupt critical autonomic life-support functions. Whereas over-dosing Huperzine A can.
Too cautious? The risk of overdosing is very low. But I want to highlight why the recommended dose of Huperzine A is measured in micrograms (1/1000 milligrams), whereas all of the other recommended doses are in milligrams.
“Long story short, the formula was written as 200 milligrams of Huperzine, rather than 200 micrograms. For those that don’t know; a microgram is 1,000 milligrams. I took 2,000 times the dose of Huperzine, and it just smacked me in the face.” Bumstead says he was incapacitated for around four hours.
Effective Difference From Huperzine A’s Inhibitory Mechanism?
Because of its inhibitory mechanism, Huperzine A can prolong neurotransmitter signal duration by slowing acetylcholine breakdown. Whereas Alpha-GPC increases acetylcholine availability by volume, not duration.4
What exactly does that mean in terms of functional benefits, and why to take it instead of another acetylcholine promoter like Alpha-GPC?
Its pharmacological justification isn’t different results, so much as faster and longer lasting results. Its higher digestive bioavailability and speed crossing the blood-brain barrier make it faster acting. And its longer half-life makes it - you guessed it - longer lasting.5
So on one hand, low differentiation plus a higher risk profile puts Huperzine A last in our direct cognitive enhancers list. I think for good reason. On the other hand, the potential for consumers to sense its impact experientially, based on the timing factors, probably is the main the reason some brands include it. But not many. And some that previously included it, have removed it in later versions.
To answer the first question, what is its place, I think its benefit lands slightly more on the seller’s side than consumer’s side. But there’s a little more too it.
Reasons To Consider Taking Huperzine A
Combining aka “stacking” Huperzine A with three other compounds listed above:
Alpha-GPC
Acetyl-L-Carnitine
L-Theanine
One triple-blind crossover trial evaluated a 10-gram dose of this multi-ingredient nootropic formula, reporting improved response times and accuracy across several cognitive tests, including processing speed, inhibitory control, spatial working memory, and cognitive agility.6
Neuroprotection
Despite its murky distinction from other acetylcholine promoters, one case in which Huperzine A shines is staving off age-related cognitive decline. It has proven to support broad-spectrum neuroprotection.7
Neurogenesis
Huperzine A stimulates the proliferation of hippocampal neural stem cells (NSCs). Which in turn can support neuroplasticity.7
I’ve tried Huperzine A in isolated powder and nootropic formulas. Here are a few of the best selling nootropic formulas that include Huperzine A.
Top Selling Formulas With Huperzine A
Brand Name | Product Name | Dosage | Stacked with |
|---|---|---|---|
Onnit | Alpha Brain Black Label | 200 mcg | +Citicoline (Alpha-GPC) |
Gorilla Mind | Gorilla Mind Smooth | 100 mcg | +Alpha-GPC |
Focus Factor | Extra Strength | ~1 of 16 for 798mg proprietary blend |
My research indicates some top selling nootropic formulas who previously included Huperzine A have since removed it. And I think we can now see why.
Personally, I’d found Huperzine A’s beneficial effects noticeably diminished after more than a week of daily consumption. Cycling seemed necessary, to me, to continue. More so than with any other compound listed here. So I stopped taking it entirely.
Though, to be fair, it’s hard to distinguish it form other ingredients, or their synergies, in a particular nootropic formula.
The Top Cognitive Enhancement Compounds deep dive series continues next week with one of many people’s favorite, but not mine: Ashwagandha.
Stay active, self-aware brains!
🫶🏽
Footnotes:
Huperzine A:
Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine. Acta Pharmacol Sin. 2006;27(1):1-26. PMID: 16364216.
https://pubmed.ncbi.nlm.nih.gov/16364216/Huperzine A: a new promising drug for Alzheimer’s disease. Acta Pharmacol Sin. 1995;16(5):391-395. PMID: 8704983.
https://pubmed.ncbi.nlm.nih.gov/8704983/Choline alphoscerate in cognitive decline and in acute cerebrovascular disease: an analysis of published clinical data. Mech Ageing Dev. 2001;122(16):2041-2055. PMID: 11719013.
https://pubmed.ncbi.nlm.nih.gov/11719013/The pharmacology of acetylcholinesterase inhibitors. Fundam Clin Pharmacol. 2002;16(5):361-373. PMID: 12460151.
https://pubmed.ncbi.nlm.nih.gov/12460151/Huperzine A improves cognitive deficits and brain function in adolescent students. Acta Pharmacol Sin. 1999;20(7):601-604. PMID: 10437131.
https://pubmed.ncbi.nlm.nih.gov/10437131/Acute Effect of a Dietary Multi-Ingredient Nootropic as a Cognitive Enhancer in Young Healthy Adults: A Randomized, Triple-Blinded, Placebo-Controlled, Crossover Trial. PMCID: PMC9133906 PMID: 35634417
https://pmc.ncbi.nlm.nih.gov/articles/PMC9133906/Huperzine A improves chronic cerebral hypoperfusion-induced cognitive deficit and hippocampal neuron damage in rats. Eur J Pharmacol. 2010.
https://pubmed.ncbi.nlm.nih.gov/10856449/
Alpha-GPC:
Acute Alpha-Glycerylphosphorylcholine Supplementation Enhances Cognitive Performance in Healthy Men (2024)
https://pmc.ncbi.nlm.nih.gov/articles/PMC11644786
Caffeine/L-Theanine:
L-Theanine and Caffeine in Combination Affect Human Cognition as Evidenced by Oscillatory alpha-Band Activity and Attention Task Performance
https://www.sciencedirect.com/science/article/pii/S0022316622099126