Huperzine A is an alkaloid compound extracted from a club moss called Huperzia serrata. It has been touted to have a number of neuroprotective and “nootropic” (cognitive-enhancing) properties, and has even suggested as a possible treatment for Alzheimer’s disease. But what does the science actually say about this plant-based supplement? Read on to learn more about Huperzine A, its potential effects, and how it might work!
What is Huperzine A?
Huperzine A (HupA) is an alkaloid compound extracted from club moss (Huperzia serrata).
Club moss (“Qian Ceng Ta”) has traditionally been used in Chinese medicine for fever, inflammation, and even schizophrenia [1, 2].
Because of its long history of use in traditional medicine, huperzine A has been studied as a compound of interest for its potential effects on a number of important systems in the body and brain. While not all of its touted effects have been validated by science, there are a number of promising early findings that may suggest some potential applications of this supplement, which we’ll review in this post.
Mechanism of Action
There are two forms of huperzine A: ‘(+)’ and ‘(-)’. The ‘(-)’ form is found naturally in the huperzia moss, and is believed to be more potent than the ‘(+)’ form.
Although the effects of huperzine A are still being actively studied by scientists, there are a few mechanisms that have been identified so far which may be responsible for some of its reported effects.
Increases Acetylcholine
Huperzine A has been reported to be a potent, reversible, and specific inhibitor of the enzyme acetylcholine esterase (ACHE). This enzyme breaks down the major neurotransmitter acetylcholine, suggesting that some of huperzine A’s effects may come from generally increased levels of acetylcholine throughout the brain [3].
For example, according to one animal study, huperzine A was reported to increase acetylcholine levels in rat brains for up to 6 hours after administration [4].
Several animal studies have reported that huperzine A may result in a more prolonged increase in acetylcholine in the whole brain when compared to other compounds that raise acetylcholine levels, such as tacrine, physostigmine, and metrifonate [5, 6, 7].
According to one study, Huperzine A may work in similar ways to some Alzheimer’s disease medications which are also believed to affect the acetylcholine system of the brain, such as donepezil, rivastigmine, tacrine, and galantamine – although with fewer side effects and somewhat more favorable pharmacokinetics [8].
This potential increase in acetylcholine levels seems to differ between different parts of the rat brain. According to a few animal studies, following administration, maximum acetylcholine levels were observed in the hippocampus after 30 min, and in the frontal and prefrontal cortex after 60 min. These observations suggest that huperzine A may influence the function of different parts of the brain at different times [6, 7].
However, some researchers have also stressed that huperzine A likely also has effects on other brain mechanisms that do not involve ACHE – so this effect alone is probably not the whole story [3].
Increases Norepinephrine and Dopamine – but not Serotonin
According to one animal study, huperzine A was reported to increase the levels of norepinephrine and dopamine in the brains of rats, while not affecting the levels of serotonin [9].
However, a lot more studies will be needed to know if these effects apply to the human brain as well.
Neuroprotective Mechanisms
Early evidence from a few studies suggests that huperzine A may have a few mechanisms that could help protect the brain from stress and harm. Some of these suggestive findings include:
- Muscarinic and GABA receptors may play a role in some of the reports that huperzine A protects against seizures (mouse study) [10].
- One literature review on huperzine A hypothesizes that it may help promote neuronal growth by stimulating the production and secretion of nerve growth factor (NGF) [3].
- One in vitro cell study proposed that huperzine A may help prevent or reduce cell damage from lack of oxygen (hypoxia). This protective effect may be partly mediated by the “cholinergic anti-inflammatory pathway” through alpha7 nicotinic acetylcholine receptors [11].
However, all of these findings come primarily from animal and cell studies, which means that they are still quite far from having been proven. A lot more research will be needed to see what role, if any, huperzine A may have in protecting brain health in normal human users.
Other Mechanisms
One animal study has reported that Huperzine A may help with inflammation in rats – in particular by reducing activities of NF-kB signaling, which may happen both through inhibition of acetylcholine esterase or in other ways [12].
Once again, though, a lot more follow-up studies will be needed to find out for sure how strong the effect is, as well as if it would apply to human users in any significant way.
Potential Effects of Huperzine A
POSSIBLY EFFECTIVE:
1) May Prevent and/or Treat Alzheimer’s Disease
In a systematic review of different interventions for Alzheimer’s, combined data from multiple studies was used to suggest that huperzine A may have a statistically significant effect in reducing cognitive decline during Alzheimer‘s disease [13].
However, while the early results are promising, there are some important limitations to note. For example, the quality of these studies is somewhat lower than the quality of studies of other medical interventions in Alzheimer’s disease and other dementia-related conditions. Many such studies are poorly-controlled or were not designed to rule out biases from the authors. In addition, most of the studies and clinical trials were from China, which raises some questions about their overall validity.
Nonetheless, according to some other researchers, huperzine A has been reported to prevent neuron loss during Alzheimer’s – specifically, by inhibiting the inflammatory responses caused by the build-up of amyloid beta, the main factor believed to be responsible for Alzheimer’s disease) [14].
In a related study, huperzine A was reported to inhibit the NF-kB pathway in immune cells in the brain. This further suggests that it may help reduce inflammation, which could account for why huperzine has been claimed to help slow down the progression of cognitive symptoms in Alzheimer’s disease [15].
At least one clinical trial in patients with Alzheimer’s disease has reported that huperzine A supplementation appeared to improve cognitive function and overall well-being in these patients [16].
Figure 1: How huperzine A may help in Alzheimer’s. Source: [17]
All in all, while the research behind these effects are still in a relatively early stage, based on what is known so far, huperzine A has been classified as “possibly effective” for the management of Alzheimer’s disease according to the Natural Medicines Database (a professional medical database for tracking the efficacy and safety of various “alternative” or “complementary” treatments for major diseases and other common health conditions).
2) May Improve Memory Function
According to some early animal studies and clinical trials in humans, huperzine A may be associated with enhancements in memory and other neuro-protective effects [16].
For example, huperzine A was reported to significantly improve memory abilities in adolescent high school students when compared to an inactive placebo treatment [18].
Although the mechanisms behind this potential effect are still unclear, one animal study reported that huperzine A may stimulate the growth of neuronal cells (neurogenesis) in the hippocampus of mice [19]. This brain region is believed to be highly involved in memory, and could potentially account for the purported memory-enhancing effects of huperzine A.
Nonetheless, many more studies will be needed to fully confirm these effects and mechanisms in healthy human users – but for now, the early results are at least promising, and huperzine A is currently considered to be “possibly effective” when it comes to supporting cognitive functions related to memory.
INSUFFICIENT EVIDENCE:
In addition to its potential applications in Alzheimer’s disease and general cognitive enhancement, huperzine A has also been studied for some of its effects in other health conditions and cognitive functions.
However, these lines of research are still highly preliminary – and while there have been some promising early results, many of the following effects are still considered to currently have “insufficient evidence” to come to any firm conclusions. Therefore, these effects and mechanisms should be taken with a grain of salt until more solid clinical research is done to verify them further.
3) May Reduce Cognitive Symptoms of Depression
While primarily a mood disorder, depression can also involve disruptions in cognitive abilities, which can be serious symptoms in their own right.
According to one preliminary study, when used as an add-on (complementary) treatment to standard antidepressants, huperzine A was reported to resolve some of the significant cognitive symptoms associated with depression – however, it did not alleviate the depression itself, suggesting that it only affected the cognitive symptoms specifically [20].
4) May Help Treat Cocaine Addiction
One early study based on self-administration of huperzine A reported that this decreased the individual’s perception of the effects of cocaine. The authors of this study proposed that huperzine A supplementation may be a safe “complementary” approach to help treat addiction [21], although much more research will be needed to verify this potential use.
5) May Help Treat Myasthenia Gravis
Myasthenia gravis is an autoimmune disease where the immune system attacks acetylcholine receptors, leading to problems with voluntary movement and muscle control. It is most commonly treated with immunosuppressants and acetylcholine esterase inhibitors [22]; however, some early studies have looked at huperzine A as a potential additional (complementary) form of treatment.
According to one preliminary clinical study with 128 patients, huperzine A was reported to alleviate muscle weakness in Myasthenia gravis patients [23]. Although this is only one study, it offers promising results that will hopefully be followed-up on and confirmed by additional clinical studies.
6) May Be Neuroprotective
Preliminary findings from some very early studies suggest that huperzine A could have a number of mechanisms that may potentially help protect brain cells from certain forms of stress and damage.
May Protect Against Toxic Organophosphates
Nerve gasses and organophosphates are irreversible inhibitors of acetylcholine esterase. Some researchers have suggested that huperzine A use may aid in preventing seizures and nervous system dysfunctions caused by soman, an organophosphate [24].
Additionally, at least one animal study has also reported that huperzine A may also help with chemical-induced cognitive impairment in mice [25].
May Protect Neurons Against Glutamate Toxicity
Glutamate is an amino acid neurotransmitter that can kill neuronal cells by overstimulating the NMDA receptors – a process called excitotoxicity. This can be especially dangerous to older neurons [26].
Huperzine A is an inhibitor (antagonist) of these NMDA receptors, which has lead some researchers to suggest that it may help prevent neurons from cell death due to glutamate toxicity [27].
May Protect the Brain From Oxidative Stress
In addition to binding to NMDA receptors, some evidence suggests that huperzine A may also help reduce oxidative damage from glutamate toxicity – specifically, by activating BDNF-dependent and mTOR signaling pathways [28].
Findings from one cell-based study suggest that huperzine A may also protect against oxidative damage from iron overload – however, this effect was only reported in vitro, and will have to be confirmed by follow-up studies in living animals and humans [29].
7) May Aid Recovery from Brain and Spinal Cord Injuries
In addition to some of the preliminary evidence suggesting that huperzine A may protect brain cells from certain types of damage, there are also a few early studies that suggest that huperzine A may also help protect the brain as a whole from certain forms of physical injury.
For example, combination treatments with huperzine A together with other supplement compounds (vinpocetine, acetyl-L-carnitine, n-acetylcysteine, and alpha lipoic acid, and fish oil), have been reported to help increase brain blood flow and improve cognitive functions in retired NFL football players with a history of concussions [30].
Unfortunately, due to the large number of compounds used in this study, it’s impossible to form any solid conclusions about which particular compound(s) might have been responsible for these results.
However, in one animal study, huperzine A was reported to decrease programmed cell death (apoptosis) as well as improve neurological symptoms in rats with spinal cord trauma [31].
According to one cell study, huperzine A may aid in recovery from brain bleeding by preventing damage to the mitochondria and postponing cell death [32]. However, follow-up studies in living animals would be needed to confirm this finding.
8) May Prevent Brain Damage from Infections (Sepsis)
Although this evidence is very preliminary, at least one animal study suggests that huperzine A may have the potential for protecting the brain during infections. In a rat model of severe bacterial infection (sepsis), huperzine A was reported to protect the brain from damage by reducing inflammation [33].
9) May Reduce / Prevent Seizures
According to some early animal research, huperzine A may be an effective treatment for epilepsy (in rats) [34].
In other animal studies, Huperzine A has been reported to protect brain cells from overexcitement and death associated with convulsions [35].
According to another study in mice, huperzine A was reported to make certain brain circuits more resistant to seizures [10].
Bioavailability
According to some studies in human users, oral huperzine A is absorbed relatively quickly, distributed widely throughout the body and brain, and is gradually eliminated or removed from circulation at a moderate rate [36].
According to an animal study (in mice), levels of huperzine A were reported to be highest in the kidney and the liver 15 minutes after injection. After 12 hours, no trace of huperzine A was found anywhere in the body [37].
After injecting mice with Huperzine A, it was found throughout all regions of the brain, particularly in the cortex, hippocampus, and nucleus accumbens [4]. Thus, this early research suggests that huperzine A is indeed capable of crossing the blood-brain barrier, meaning that it is reasonable to believe that taking it results in it actually getting to the brain (where it could have some of the cognitive effects described in the previous sections of this post).
Some evidence also suggests that huperzine A is capable of reaching the placenta [37]. Although no direct studies of its effects in pregnancy have been done yet, this preliminary finding suggests that caution may be warranted if taken during pregnancy, as its safety is not known. As always, the best way to manage considerations such as these is to make sure you talk to your doctor before trying out huperzine A (or any other new supplements or medications).
In mice, 73% of huperzine A was reported to be excreted in urine 24 hours post-injection, while only 2.4% of the ingested amount was found in feces [37]. This early finding suggests that it is eliminated from the body fairly rapidly, and probably does not pose too much of a risk of building up to dangerous levels if taken for extended periods – nonetheless, more studies in human users will be needed to know for sure, so this should not be considered a definitive finding until more research is done.
Dosage
According to one human study, it was reported that a very high dose (1mg) caused peak serum (blood) concentration of huperzine A to be reached at approximately 80 minutes post-ingestion. Additionally, half of huperzine A was found after approximately 288 minutes (roughly 5 hours), suggesting that it may be necessary to take huperzine A multiple times a day to achieve steady, continuous levels throughout the body [36]. Nonetheless, this dosage information is based only on a single study so far, so it shouldn’t be considered definitive until additional studies in human users are done.
No build-up of tolerance (loss of biological sensitivity to the compound) has been reported from repeated or continued use from huperzine A, at least according to one early study [38].
Dosages in clinical trials for Alzheimer’s range from 0.2 mg to 0.8 mg [39].
However, for Alzheimer’s patients, one study reported that a dosage of 0.4 mg twice daily was required to produce clinically-significant results, while 0.2 mg twice daily did not [40].
In high school students who struggle with memory, just 0.1mg was reported to be sufficient to produce detectable effects on memory ability [18].
All in all, the research so far is still very preliminary, so it’s difficult to say with certainty what the best dosage for supplementing might be. Based on what we know, it may depend on what the desired effects are, and who exactly is taking it – but in any case, the safest bet is to always start small, and only increase the dose gradually.
Side-Effects
Not much clinical research has been done on this compound, so what we know about huperzine A’s potential side-effects is highly limited.
As always, make sure to discuss any new supplements you’re considering taking with your doctor first. Also make sure that he or she is fully up-to-date about any other medications you’re currently taking, any other pre-existing health conditions you have, and any other lifestyle or dietary factors that may impact your health or medical treatment.
With that in mind, the early evidence available so far suggests that adverse side-effects are relatively rare. For example, no notable side-effects were observed at doses between 0.18-0.54 mg, at least according to one study of human users [36].
However, some other studies have reported occasional side-effects, including “cholinergic symptoms” such as dizziness, nausea, digestive upsets, headache, and decreased heart rate [8].
Drug Interactions
Once again, hard data about huperzine A’s potential interactions is mostly unavailable, due to a lack of extensive clinical testing.
One of the only available studies on its potential interactions reports that huperzine A is unlikely to interact with cytochrome P450 (an enzyme involved in “detoxing” drugs and other foreign compounds from the body). For example, cell studies using human liver cells have shown that huperzine A is excreted whole, which suggests that it may be unable to react with other drugs that are metabolized by the cytochrome P450 system [41].
Nonetheless, the best way to minimize your risk of experiencing adverse interactions is to discuss any new supplements with your doctor first, who will use their detailed medical expertise to help you manage any potential unforeseen interactions.
