May 18, 2021 18 min read

The BetterMind Nootropic Stack by Betterbrand

A guide to understanding how nootropics work, and how the BetterMind Nootropic Stack promotes all-day-energy, aids memory and recall, and helps you focus. 

Written By: Dr. Chris Jackson, PharmD

Introduction

This document should act as a beginner's guide to nootropics as well as a detailed guide regarding the ingredients and thought process behind the BetterMind Nootropic Stack by Betterbrand.

Why BetterMind Nootropic Stack?

The BetterMind Nootropic Stack began as a passion project while two classmates were pursuing their doctorates. One, a neurobiologist and the other, a biochemist. The goal was to identify natural (existing in and extracted from nature), semi-synthetic (existing in nature but manufactured through synthetic pathways), and synthetic (existing and manufactured only through synthetic pathways) ingredients that could support the heavy workload associated with the program. Not only that, but identifying compounds that could potentially enhance the ability to maintain attention over extended periods of time could have potentially profound importance in the everyday life of individuals all over the world where lapses in attention are a common occurrence. That’s where nootropics come in. 

What are Nootropics?

It depends on who you ask. “Nootropic” is the term used to describe “smart drugs,” although most are not considered drugs and do not require a prescription. Of course, regulations vary from country to country. 

There are two generally accepted definitions. The original definition, established by Dr. Corneliu E. Giurgea, Romanian psychologist and chemist considered to be the founding father of nootropics, and the common definition.¹

Dr. Giurgea was the first to attempt a descriptive criteria for what qualifies as a nootropic, which includes:

  1. Enhancement of memory and learning
  2. Improved cognition under stress
  3. Protection of brain cells (e.g. the compound has neuroprotective properties)
  4. Facilitation of cell-to-cell communication
  5. Backed by human research demonstrating brain bioactivity
  6. Absence of usual pharmacological effects (to include side effects) of psychotropic drugs

Using the original definition, it is hard to imagine a compound that provides benefit and lacks pharmacological effects of psychotropics as it is difficult to separate the impact on behavior, mood, perception, and thoughts related to productivity from the compound itself. 

The common definition is any compound that boosts productivity, memory formation, and a host of other cognitive functions. 

What is a Nootropic Stack?

A “stack” is the term for the combination of two or more nootropic ingredients. Most times (but not always), the goal is synergy. For example, the combination of caffeine and L-theanine is the most basic and common example. Theanine acts as an anxiolytic to balance out the jittery effects of caffeine, and they are generally dosed in a 2:1 ratio. 

Ingredient Categories

There are various categories that nootropic ingredients can fall into, and some are open for debate:

  • Cholinergics
  • Stimulants
  • Racetams
  • Adaptogens
  • Miscellaneous

In general, cholinergics upregulate acetylcholine (ACh), stimulants increase activity in the sympathetic nervous system (SNS), racetams work in a number of ways to include acting on the parasympathetic nervous system (PNS), and adaptogens work to support the body’s response to environmental and non-specific stress. The categories are listed in table 1 based on their mechanism of action. 

Table 1: Nootropic Ingredients by Category

Category*

Ingredient Examples

Cholinergics*

Huperzine A, Alpha GPC, Citicoline

Stimulants*

Caffeine, Theobromine, Theacrine, Armofinil, Modafinil, Methylphenidate, Amphetamine

Racetams*

Piracetam, Oxiracetam, Phenylpiracetam, Aniracetam

Adaptogens*

Ginseng, Rhodiola, Schisandra 

Miscellaneous*

Bacopa, Theanine, Lion’s Mane, ISRIB

*Not an all-inclusive list

Prescription only in the US

Not considered prescription drugs or dietary supplements in the US and cannot be labeled as such

Cholinergics

“Cholinergics” are any compound that acts on cholinergic synapses, which are ubiquitous throughout the central nervous system (CNS). Their high density in various parts of the brain to include the limbic system (e.g. the hypothalamus involved in homeostasis, the amygdala involved in mood and emotion, and the hippocampus involved in memory consolidation), suggest that cholinergic transmission is critical for memory, learning, attention, and other higher brain functions. Research suggests additional roles for cholinergic systems in overall brain homeostasis and plasticity. With that in mind, the brain’s cholinergic system occupies a central role in ongoing research related to cognition.² 

Stimulants

The word “stimulant” usually refers to agents stimulating the CNS with an effect on alertness, locomotion, and mood, or generally targeting the SNS. This can elicit the well known fight-or-flight reaction to increase blood flow to skeletal muscles, and mobilize energy. Stimulants can include compounds that increase alertness and reduce fatigue, such as coffee. Others, such as amphetamines, can affect mood and modify mental alertness. The majority of stimulants act on the monoaminergic systems and are listed in table 2.³ 

Table 2: Stimulant Ingredients by Category

Category*

Neurotransmitter

Sympathomimetic

Norepinephrine (NE), Epinephrine (Epi)

Dopaminergic

Dopamine (DA)

Serotonergic

Serotonin (5-HT)

*Not an all-inclusive list

Sympathomimetic is a term used to describe agents that mimic sympathetic/adrenergic responses 

Less commonly used phrases dopaminomimetic and serotoninomimetic could be used to describe actions on the DA and 5-HT systems 

Racetams

While a number of racetams are commercially available, they are considered “research only” products and cannot be sold as dietary supplements, or included in pre-mixed stacks like BetterMind Nootropic Stack in the US market. 

Racetams share a common structural feature, a pyrrolidinone ring. Nootropics developed from pyrrolidinone derivatives have common features such as enhancing the learning process, diminishing impaired cognition, as well as neuroprotective properties - fitting the classic definition perfectly as piracetam was discovered by Dr. Giurge. Studies support the role of piracetam in enhancing memory and learning, as well as acting synergistically with choline. This makes sense as the administration of piracetam impacts the ACh receptor binding in various brain regions.⁴ Alternatively, racetams may act on the AMPA receptor, which glutamate binds to. Glutamate is often referred to as the “gas pedal” or the principal excitatory neurotransmitter in the CNS.⁵ Despite having a low affinity for glutamate receptors, piracetam initiates a number of effects: activation of AMPA receptors, increasing the density of AMPA receptors in the synaptic membrane of the cortex, and the release of glutamate itself. In short, research suggests the neuroenhancing effects of piracetam are via stimulation of ACh and glutamatergic systems.⁴

Adaptogens

During World War II, the idea that a pill could improve mental and physical performance in healthy people was devised and various stimulants were given to pilots and members of submarine crews prior to the formal definition of nootropics. Adaptogens were initially defined by Nikolay Lazarev as substances that enhance the “state of nonspecific resistance” in stress based on Hans Selye’s theory of stress and general adaptation syndrome. Studies on animals and humans support that adaptogens exhibit neuroprotective, anti-fatigue, anxiolytic, and CNS stimulating properties. In essence, they combine elements from several of the categories of nootropics. In addition, a number of clinical trials have demonstrated that adaptogens exert an anti-fatigue effect that increases mental work capacity against the background of stress and fatigue, particularly in tolerance to mental exhaustion and enhanced attention.⁶

A few recognizable herbs classified as adaptogens are ginseng,Rhodiola, andSchisandra, all of which are detailed below. 

ThePanax genus (ginseng) of herbs contains several species such as Korean ginseng (Panax ginseng) and American ginseng (Panax quinquefolius) that are relatively well-known. Ginsenosides such as Rb1, Rd, Re, Rg1, Rg2, Rg3, Rh1, Rh2, Rh3, PF11, and NTR1, and gintonin and compound K, are the active components within the ginseng plant responsible for its qualities.⁷ However, other plants are sometimes referred to as ginseng, such as Siberian “ginseng” (Eleutherococcus senticosus), however, eleutherosides are the active compounds in this plant. In both animal and cellular models, ginsenosides are responsible for activity against oxidative stress and exert their effects by modulating cholinergic, glutaminergic, and other molecular signaling pathways that are vital for cognitive activity.⁷

Rhodiola rosea has been observed to increase the levels of NE in the cerebral, prefrontal, and frontal cortex regions of the brain while also upregulating DA and ACh in the limbic system pathways.⁴ With that underlying mechanism in mind,Rhodiola can improve attention when fatigued after single and repeated administration and has been observed to do so when experiencing physical, emotional, and mental exhaustion.⁶˒ 

Schisandra chinensis has been reported to be effective in relation to reduced physical and mental performance in open label studies, showing improvement after 2–10 weeks of use. In particular, an increase in general well-being and work capacity, as well as a decrease in sleepiness and exhaustion has been observed.⁶

It is the opinion of the science team at Betterbrand that these natural products, which exhibit nootropic properties, will be more useful in a future mood-balancing dietary supplement product instead of inclusion in the current BetterMind Nootropic Stack. 

Miscellaneous

There are a number of ingredients that do not fit neatly into other categories. The following details a few select ingredients of interest that are not currently available in our nootropic stack. 

Bacopa monnieri has been studied preclinically and clinically with some statistically significant findings relating to retention of new information. The effects were attributed to antioxidant action in the hippocampus region of the CNS.⁹ Bacopa monnieri is also known for anxiolytic effects.⁴

Hericium erinaceus, commonly referred to as Lion’s Mane, is a fungus with a long history of use. It contains bioactive metabolites that can be classified into high molecular weight compounds, typically as polysaccharides, and low molecular weight compounds, typically polyketides and terpenoids. These compounds are thought to have neuroprotective properties and to promote nerve growth factor gene expression.¹⁰ In behavior testing on mice, supplementation with Lion’s Mane induced a statistically significant improvement in short-term memory and visual recognition. In a double-blind placebo-controlled clinical trial in humans with mild cognitive impairment, supplementation with Lion’s Mane for 16 weeks was associated with improvement in cognitive function compared to controls.¹¹

Integrated stress response inhibitor (ISRIB) is an experimental drug that inhibits a key step in the integrated stress response (ISR) associated with cognitive deficits. Animals with more inhibition of this key step show enhanced long-term memory storage, and those with less inhibition have trouble forming long-term memories.¹² Research is still underway on this ingredient. 

Ingredient Background

The background and mechanisms associated with ingredients used in the BetterMind Nootropic Stack will be detailed further in the following section. 

Huperzine A

Huperzine A is an alkaloid isolated from certain species in the Lycopodium family, including the Chinese club moss, also known as the toothed clubmoss (Huperzia serrata), and fir clubmoss (Huperzia selago). Huperzine A was identified, purified, and formulated for medicinal use by scientists at the Chinese Academy of Sciences in the 1980s. It is now approved as a prescription drug in China.¹³

The primary mechanism of action of huperzine A was determined to be a reversible, potent, and selective inhibitor of acetylcholinesterase (AChE).¹⁴ What that means is that huperzine A has the potential to increase the half-life of ACh, allowing the neurotransmitter to act in the neural synapse longer than it otherwise would. Combining that with a choline supplement like alpha GPC has the potential to upregulate the cholinergic system associated with memory formation and cognitive function.

The standard dietary supplement ingredient contains 1% of the active HupA compound, a natural ingredient.

Alpha GPC

Alpha GPC (L-Alpha glycerylphosphorylcholine) is a compound naturally produced in the body and contains the choline precursor to the neurotransmitter ACh. Alpha GPC is a lecithin molecule, phosphatidylcholine to be specific, minus the two attached fatty acids. In some parts of Europe, alpha GPC is approved as a prescription drug for brain health under the name choline alfoscerate.¹⁸

The primary mechanism of action of alpha GPC is to serve as a prodrug to choline and glycerophosphate. With this, it has the potential to directly increase both the synthesis and the release of ACh, and to serve as a precursor for membrane phosphoIipids, which can improve the fluidity and functionality of the neuronal membrane.¹⁵

The standard dietary supplement ingredient contains 50% of the active alpha GPC compound, a natural or semi-synthetic ingredient.

Caffeine

Caffeine is a naturally occurring methylxanthine (a purine alkaloid) compound found in the leaves, seeds, or fruits of various plants, including coffee (Coffea arabica) beans, cacao (Theobroma cacao) beans, guarana (Paullinia cupana) berries, tea (Camellia sinensis) leaves, and many more plant species. 

The primary mechanism of action of caffeine is non-selective adenosine antagonist. By blocking adenosine receptors, caffeine can reverse the depressive effects of adenosine on the CNS in a dose-dependent manner.¹⁶ Caffeine can also increase the amount of Epi and NE secreted by the adrenal medulla, as well as increasing DA levels. Increases in these neurotransmitters, referred to as catecholamines, have multiple effects throughout the body and affect a number of performance variables, such as accuracy, reaction time, and overall vigilance.¹⁷

The standard dietary supplement ingredient contains 100% of the active caffeine compound, a natural or semi-synthetic ingredient.

L-Theanine

Theanine (gamma-glutamylethylamide), a major non-protein amino acid found in tea, is chemically similar to glutamate and was first isolated from green tea in the 1940s. 

The primary mechanism of action of theanine is related to its anxiolytic effects, which are in part due to its effects on glutamate receptors.¹⁸ Theanine is thought to balance out the jitters associated with caffeine use due to these effects, and the two are often combined in a 2:1 (two parts theanine, one part caffeine) ratio.

The standard dietary supplement ingredient contains 100% of the active theanine compound, a natural or semi-synthetic ingredient.

Theacrine

Theacrine, a purine alkaloid, is structurally similar to caffeine and was first discovered inCamellia sinensis leaves in the 1930s. Large quantities of theacrine are present in the tea plantCamellia assamicavariantkucha also referred to as “Kucha Tea”. 

The primary mechanism of action of theacrine, similar to caffeine, is to act as an adenosine receptor antagonist. Theacrine has also been shown to increase DA levels.¹⁹˒²⁰

The standard dietary supplement ingredient contains 40% of the active theacrine compound, a natural or semi-synthetic ingredient.  

Beta-Hydroxybutyrate (BHB)

BHB is a type of ketone body that is produced by the liver from fatty acids as a source of energy when carbohydrate intake is low and is found in very low levels in the blood of healthy individuals. It is also a popular ingredient associated with the ketogenic diet with many users claiming mental clarity as one of the benefits. 

The mechanism of action responsible for BHB’s effect on cognition is unclear at this time. Observed rapid improvement in some areas of cognitive functioning following acute elevation in BHB levels suggests that ketones may function as an alternative fuel for cerebral neurons when glucose uptake is impaired.²¹

The standard dietary supplement ingredient contains varying amounts of the active BHB compound in calcium, magnesium, potassium, or sodium salt forms. BHB is a natural or semi-synthetic ingredient.

Clinical Trials

Huperzine A

Huperzine A has been studied extensively in human clinical randomized controlled trials. A meta-analysis, which is a compilation of all available quantitative data based on a pre-specified search criteria, and a systematic review, a similar compilation of qualitative data, were published in 2013 and 2016, respectively.¹⁴˒²² The focus of a majority of the trials was cognitive function, and huperzine A showed a statistically significant difference when compared to placebo in a majority of the trials.¹˒²²

There is some concern surrounding clinical dosing of huperzine A based on reports of gastrointestinal discomfort or nausea following administration of clinical doses. This is the case in a number of competitor products. With this in mind, sub-clinical dosing of huperzine A is utilized in the BetterMind Nootropic Stack. 

Alpha GPC

Alpha GPC has been studied extensively in human clinical randomized controlled trials. One such study tested the effects of alpha GPC on memory impairment induced by scopolamine, an anticholinergic agent that counters the neurotransmitter ACh in the CNS. The findings indicate that alpha GPC was able to antagonize impairment of attention and memory induced by scopolamine.²³ A separate study showed that, compared with placebo, supplementation with alpha GPC  significantly improved cognition and global function in study participants.² 

When considering choline supplementation, there was a decision to be made regarding the inclusion of alpha GPC or citicoline (CDP-Choline) in the BetterMind Nootropic Stack. While the tolerability of both is comparable, alpha GPC was confirmed in psychometric tests to be superior to citicoline in improving memory functions in at least one study.¹⁵ 

Again, there is some concern surrounding clinical dosing of alpha GPC based on reports of gastrointestinal discomfort or nausea following administration of clinical doses. This is the case in a number of competitor products. With this in mind, sub-clinical dosing of alpha GPC is utilized in the BetterMind nootropic stack. 

Caffeine

Caffeine has been studied extensively in human clinical randomized controlled trials. Caffeine has been found to reduce omission and commission errors, and decrease reaction times. These findings were observed in conjunction with reduced tonic alpha-band activity, suggesting improved attentional processing.²⁵ In a separate study, theanine, caffeine, and the combination of the two significantly improved recognition visual reaction time. When compared to a placebo, theanine alone, caffeine alone, and the theanine/caffeine combination elicited greater stimulus discrimination and inhibition of responding to distracters.²⁶ 

Due to the potential of caffeine to increase catecholamines such as Epi and NE, as well as the potential for dependence,¹⁷ dosing caffeine appropriately in the BetterMind Nootropic Stack and keeping the amount to less than a single cup of coffee was an important consideration. 

L-Theanine

Theanine has been studied extensively in human clinical randomized controlled trials. Theanine has been found to reduce omission and commission errors, however, differing from caffeine, theanine was not found to reduce reaction times and was not accompanied by changes in alpha-band activity in one study.² In a separate study, theanine was found to improve cognitive functions, specifically decreased response latency and error rates, and improved verbal memory and executive functions.¹⁸

Due to the desire to minimize the negative effects associated with caffeine consumption and promote a jitter free experience, theanine and caffeine were combined in a 2:1 ratio in the BetterMind nootropic stack. 

Theacrine

Theacrine, while existing in nature, is relatively new as a dietary supplement compared to other ingredients in the BetterMind Nootropic Stack. New evidence is continuously emerging to support its use. In one study, theacrine displayed a modest increase in cognitive benefit when combined with caffeine during complex decision making, with similar benefits observed in time to exhaustion.²⁶

In an effort to minimize SNS overload, special care went into ensuring that there were no caffeine or caffeine-like effects hidden in other ingredients (e.g. guarana combined with caffeine despite its naturally high caffeine content) related to jitters or hemodynamic response. With that in mind, a separate study observed that theacrine did not alter hemodynamic measures, such as heart rate, and there was no evidence of tachyphylaxis (diminishing response) with consistent use.²⁰ This study and internal testing assured the team that theacrine could be combined with caffeine in the BetterMind Nootropic Stack.

BHB

BHB, while existing in our own bodies, is relatively new as a dietary supplement compared to other ingredients in the BetterMind Nootropic Stack and is not generally considered a nootropic. It has, however, been studied for its impact on cognitive function. In one study, results indicate that cognitive improvements were observed in response to acute elevation of BHB levels following supplementation with medium-chain triglycerides. These elevations were associated with improved cognitive facilitation and paragraph recall.²¹ In general, factors impeding glucose utilization by the brain may contribute to reduced cognitive function. In situations such as this, BHB and other ketone bodies can account for greater than 60% of the brain's energy demands.²⁸

Due to the desire to minimize the gastrointestinal discomfort that can accompany oral supplementation with high-dose BHB salts, it was determined that a very low dose was required in the BetterMind Nootropic Stack. 

Safety and Absorption

Huperzine A

Following oral ingestion, huperzine A is absorbed rapidly, crosses the blood-brain barrier, and reaches peak concentrations in 60-80 minutes.²⁹˒³⁰ In animal research, overall bioavailability is estimated at 96.9%.³¹

There is some concern in the supplement industry, however, that dosing at levels used in clinical trials may lead to an undesirable side effect profile; a common feature of competing products. With that in mind, sub-clinical dosing is used to balance the side effects with the benefit received following supplementation. 

Alpha GPC

Alpha GPC has GRAS status in the US up to 196.2mg per day.³²˒³³ Alpha GPC is rapidly absorbed with an increased free choline plasma level observed 60 minutes after oral administration of alpha GPC, and maintained at 120 minutes, representing an increase of 38% to 51% over basal levels.³⁴

There is some concern in the supplement industry, however, that dosing at levels used in clinical trials may lead to an undesirable side effect profile; a common feature of competing products. With that in mind, sub-clinical dosing is used to balance the side effects with the benefit received following supplementation.

Caffeine

Caffeine has GRAS status in the US.³²˒³³ Caffeine is rapidly absorbed, oral bioavailability is essentially 100%, it crosses the blood brain barrier, and reaches peak concentration 15-120 minutes after oral ingestion.³⁵˒³⁶ Daily intake of caffeine should not exceed 400mg/day in healthy adults.³⁵

L-Theanine

Theanine has GRAS status in the US up to 250mg per serving.³²˒³³ Theanine is rapidly absorbed, and reaches peak concentration at 45-60 minutes.³

Theacrine

Theacrine has GRAS status in the US.³²˒³³ Theacrine is rapidly absorbed, crosses the blood brain barrier, and reaches peak concentration in under two hours following oral ingestion. In addition, the pharmacokinetic parameters of theacrine and caffeine are not altered when co-administered, and hemodynamic response is similar to the administration of caffeine alone.²⁰˒³

BHB

Oral administration of BHB salts rapidly increases blood levels of BHB over 15 to 120 minutes.³⁹˒⁴⁰

Excessive dosing of ketone salts may lead to an undesirable side effect profile. With that in mind, low dose ketone salts are used to balance the side effects with the benefit received following supplementation.

Conclusion*

Several independent trials have been conducted suggesting the compounds included in the BetterMind Nootropic Stack act on the CNS to promote all-day-energy, aid memory and recall, and help you focus. *These statements have not been evaluated by the Food and Drug Administration. This product is not intended to treat, diagnose or cure any disease.

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