Qualia Mind: The Building of a Nootropic Stack

Introduction to Qualia Mind

Qualia Mind® is a nootropic containing a selection of compounds with nootropic actions that include brain nutrients, vitamins, minerals, amino acids, choline donors, plant adaptogen extracts, a nootropic mushroom, caffeine sources, antioxidants, and mitochondrial nutrients. Qualia Mind was designed by taking into account key neural pathways and processes. Our ingredients were selected based on their stand-alone actions, but also on their additive actions when combined—how they may complement each other in supporting a particular cognitive pathway or process. We invite you to read Qualia: The Complex Intelligence Behind Its Formulation and Qualia Formulating Principles to better understand some of the thought processes behind our formulation approach. In this article, we want to share how individual ingredients in Qualia Mind stack together to support a particular pathway (e.g., acetylcholine signaling, dopamine signaling) or process (e.g., neuroplasticity, cerebral blood flow).* 

Choline Pool and Acetylcholine Signaling

Supporting pathways and processes that overlap with choline-related signaling is the foundation of a great nootropic stack. Choline and its metabolites have two main roles in the brain: neurotransmission, as acetylcholine, and cell membrane structure, as the phospholipid phosphatidylcholine. 

Choline is an essential nutrient. Although humans can produce a small amount of choline in the liver, it’s primarily provided by the diet. Without adequate levels of choline in the brain (and the ability to use it well), neurotransmission and cell membrane health are likely to be affected. 

Key goals of our design of this stack included: (1) augmenting the choline pool; (2) choosing choline sources and other nutrients that give full choline pathway support; (3) optimizing acetylcholine turnover (i.e., recycling and breakdown); and (4) supporting balanced signaling. But to provide adequate cholinergic support, it’s important to understand what happens to dietary choline in our body. 

The main fate of dietary choline is the synthesis of phosphatidylcholine. This occurs via the cytidine diphosphate-choline (CDP-choline) pathway (or Kennedy pathway), which plays a central role in choline homeostasis [1]. Phosphatidylcholine accounts for around 95% of the total choline pool in most tissues. 

In the CDP-choline pathway, choline is initially converted to phosphocholine by choline kinase (CK), using ATP (the energy currency of cells) as a phosphate donor. Magnesium is a cofactor for this enzyme reaction. Next comes the rate-limiting step of the pathway (i.e., the slowest step in the pathway so akin to a bottleneck): an enzyme called CTP:phosphocholine cytidylyltransferase (CCT) uses cytidine triphosphate (CTP) to convert phosphocholine into CDP-­choline (also known as citicoline). Qualia Mind includes Citicoline (as Cognizin®) because it can enter the pathway prior to phosphatidylcholine, is the choline form produced after the rate-limiting step, and can cross the blood-brain-barrier.* 

In the last step in the pathway, CDP­-choline is esterified with diacylglycerol (DAG) by cholinephosphotransferase (also called choline/ethanolamine-phosphotransferase [CEPT]) to produce phosphatidylcholine, the end product of the CDP-choline pathway. Since most choline in the body and brain is in the form of phosphatidylcholine, it can serve as a reservoir or pool for choline. 

Free choline and choline metabolites can then be regenerated by the controlled breakdown of phosphatidylcholine. The main routes for phosphatidylcholine breakdown are via phospholipases that hydrolyze the two acyl chains of phosphatidylcholine to yield free fatty acids and alpha-glycerophosphocholine (alpha-GPC). The subsequent hydrolysis of alpha-GPC into glycerol 3-phosphate and choline is catalyzed by glycerophosphodiesterase (GDE) according to cellular needs.  

Qualia Mind includes Alpha-GPC as an additional form of choline, as part of our goal of whole pathway support. Alpha-GPC supports the delivery of choline to the brain because it can cross the blood-brain barrier.* Choline in the alpha-GPC form can enter and augment the choline pool after phosphatidylcholine. Since enzyme reactions in the choline pathways tend to be bidirectional (i.e., they can flow in either direction), more availability of this intermediate may allow phosphatidylcholine to be used for other purposes (rather than being broken down to augment choline pools) [2,3]. By supplying choline in the alpha-GPC form, we are supplying a form of choline that can be used in the brain to form free choline, but which enters the choline pool at a different point in the pathway.*

Given the different kinetics (i.e., absorption and metabolism) and different places these ingredients can interact with choline pathways, including both Alpha-GPC and Citicoline as Cognizin® for choline support promotes the upregulation of the CDP-choline pathway and turnover of the choline/phosphatidylcholine cycle, ultimately supporting a higher availability of choline for acetylcholine synthesis and other uses.* Because of their complementary actions, this combination allows us to use lower amounts of each.

When we designed this stack, we also chose to include Phosphatidylserine, another membrane phospholipid that can be synthesized from phosphatidylcholine [4]. Supporting phosphatidylserine may help spare the use of phosphatidylcholine for its synthesis, resulting in more phosphatidylcholine availability for choline regeneration and, consequently, acetylcholine production. Furthermore, phosphatidylserine may be used to promote healthy cell membranes.* 

Choline is also a precursor for the neurotransmitter acetylcholine, which plays a key role in enhancing alertness (when we wake up), sustaining attention, and promoting healthy learning and memory [5]. Neurons that produce acetylcholine are referred to as cholinergic. Acetylcholine is produced in nerve terminals of cholinergic neurons from choline and acetyl groups provided by acetyl­-coenzyme A (acetyl­-CoA). The availability not only of choline but also of acetyl­-CoA can greatly influence the brain’s ability to produce acetylcholine. 

Coenzyme A is naturally synthesized from pantothenate (vitamin B5) [6]. CoA is then acetylated to form acetyl-CoA, predominantly via the mitochondrial pyruvate dehydrogenase complex, which consists of 3 enzymes that convert pyruvate (a key intermediate in several metabolic pathways) into acetyl-CoA—vitamins B1 (thiamin) and B3 (niacin) are needed for this complex. Vitamin B5 as Calcium Pantothenate was added to this stack to support the biosynthesis of CoA. Vitamin B1 activity is supported by Thiamine HCl, while vitamin B3 activity is supported by Niacinamide. In vitro evidence suggests that acetyl groups from compounds such as Acetyl-L-Carnitine or N-Acetyl-L-Tyrosine might contribute to acetylcholine synthesis [7].* 

Acetylcholine synthesis is catalyzed by the enzyme choline acetyltransferase (ChAT), which transfers the acetyl group from acetyl-CoA to choline [2]. ChAT is the rate-limiting enzyme step in acetylcholine synthesis. Increasing the availability of neuronal choline and acetyl groups is crucial to support acetylcholine synthesis, but it’s also important that ChAT activity be able to keep pace with demands. Polygala tenuifolia Root Extract and Terminalia chebula Fruit Extract (in Nutricog®) were included in this stack because they support the activity of ChAT, and consequently, the output of acetylcholine [8,9].*

Acetylcholine exerts its effects by activating two main classes of receptors. The first type are nicotinic acetylcholine receptors (nAChR). These are ligand-gated ion channels (i.e., ionotropic; opening to let charged minerals called ions pass through cell membranes) permeable to sodium (Na+), potassium (K+), and calcium (Ca2+) ions, whose activation causes a fast depolarization and excitation. Magnesium, in its ion form Mg2+, facilitates the balance of ion flows into cell membranes through the nAChR ionotropic receptors. Phosphatidylserine also promotes ionotropic acetylcholine receptor function and supports acetylcholine release [10,11].* The second type are muscarinic acetylcholine receptors (mAChR). These are G protein-coupled receptors (i.e., metabotropic; acting through intracellular signaling molecules called second messengers) that activate signaling pathways inside cells. Both classes of acetylcholine receptors participate in the mechanisms of memory. 

In contrast to most other neurotransmitters, the synaptic action of acetylcholine is not terminated by reuptake. Instead, cleanup is done exclusively through enzymatic hydrolysis (i.e., inactivation) by acetylcholinesterase (AChE) to yield choline and acetate. The free choline can then be taken up again by the synaptic terminal and recycled to acetylcholine (i.e., starting the synthesis process again). Polygala tenuifolia Root Extract [12–14], Terminalia chebula Fruit Extract (in Nutricog®) [9,15,16], Saffron Stigma Extract [17,18], and Celastrus paniculatus Seed Extract (as SmartSeed™) [19] may help oppose the activity of AChE, leaving more acetylcholine available to produce greater receptor stimulation and thereby helping to enhance the effects of acetylcholine.* 

Cholinergic signaling might also be enhanced by other mechanisms. For example, adenosine (a sleep-inducing factor) is a neuromodulator that reduces cholinergic activity. Blocking adenosine receptors with antagonist molecules can counter adenosine’s effects, supporting the activity of acetylcholine [20]. Caffeine is a non-selective and high-affinity adenosine receptor antagonist (the wakefulness-promoting activity of coffee is believed to be related to this effect) and might indirectly enhance cholinergic activity [20,21].* Ginkgo biloba Leaf Extract (a neuroadaptogen) also appears to have supportive and regulatory effects on aspects of acetylcholine signaling [22,23].*

Dopamine Signaling

Dopamine is one of the main neurotransmitters in the brain. It is most commonly recognized for its role in reward, motivation, and pleasure, but it also plays a crucial part in modulating focus, motivation, cognitive flexibility, and emotional resilience. In addition to these creative-productive capacities and states, dopamine is one of the main regulators of motor control and coordination of body movements.

Key parts of designing a dopamine stack are: (1) augmenting the precursor pool of compounds used to make it; (2) giving full pathway support; (3) supporting enzyme function involved in dopamine synthesis, signaling, and cleanup; and (4) promoting balanced signaling. 

Dopamine is synthesized both at the nerve terminals and in the cell bodies of dopaminergic neurons. Because it does not cross the blood-brain barrier, it must be synthesized in the brain from precursor molecules. There are three key precursor molecules in the dopamine synthesis pathway that can get into the brain: L-phenylalanine, L-tyrosine, and L-DOPA. Dopamine can be made starting from any of these molecules, with the molecules entering the pathway at different points, as the biosynthesis pathway progresses from L-Phenylalanine → L-Tyrosine → L-DOPA → Dopamine.

We included N-Acetyl-L-Tyrosine as a supplemental source of L-tyrosine. Since it can be synthesized from L-phenylalanine by phenylalanine hydroxylase (PAH), L-tyrosine is considered conditionally essential. Under certain circumstances (e.g., high stress, cognitive demands) where the body might not be able to make enough to meet demands, it becomes important to get more L-tyrosine from the diet.* 

The rate-limiting step in the dopamine synthesis pathway is the enzymatic step that turns L-tyrosine into L-DOPA, catalyzed by the enzyme tyrosine hydroxylase (TH). We included a few ingredients that support the activity of TH: Rhodiola rosea Root Extract [24–26], Ginkgo biloba Leaf Extract [27–29], and Saffron Stigma Extract [30–32]. Therefore, this stack supports the rate-limiting enzymatic step in dopamine synthesis through two different approaches—by supporting the substrate L-tyrosine and supporting the activity of the enzyme TH.*

L-DOPA is converted to dopamine by aromatic-L-amino-acid decarboxylase (AAAD, also known as DOPA decarboxylase [DDC]) with Pyridoxal-5’-Phosphate (the active form of Vitamin B6, included in this stack) as the coenzyme [33]. Rhodiola rosea Root Extract may also support the activity of AAAD [24].* 

Dopamine is used as a precursor in the synthesis of the monoamine neurotransmitters norepinephrine and epinephrine. Dopamine is converted into norepinephrine by the enzyme dopamine β-hydroxylase (DBH), with L-ascorbic acid (vitamin C) as cofactor; norepinephrine is then converted into epinephrine. Vitamin C as Ascorbic Acid was included to support the conversion of dopamine to norepinephrine by DBH. Rhodiola rosea Root Extract may also support the activity of DBH [24].*

Insufficiencies in any precursor amino acid or any cofactor in the catecholaminergic anabolic pathways can therefore impair the synthesis of all three catecholamine neurotransmitters—dopamine, epinephrine, norepinephrine. 

After synthesis, dopamine is transported into synaptic vesicles. Once released into the synaptic cleft, dopamine exerts its actions by binding to and activating dopamine receptors in postsynaptic or presynaptic neurons. Dopamine activity is terminated by being retaken up into the presynaptic cell or surrounding glial cells by the dopamine transporter (DAT). Oroxylum indicum bark extract (as Sabroxy®)  [34], Polygala tenuifolia Root Extract [35], and Saffron Stigma Extract [36] may help oppose DAT activity and therefore lessen dopamine reuptake, allowing it to linger in the synaptic space and produce greater receptor stimulation, which might help to enhance its actions.*

After reuptake, dopamine is degraded into inactive metabolites by a sequence of reactions catalyzed by monoamine oxidase (MAO), followed by aldehyde dehydrogenase (ALDH), and catechol-O-methyltransferase (COMT) (a magnesium-dependent enzyme). Reducing MAO activity may extend the availability of dopamine in neurons, an action that may be supported by Rhodiola rosea Root Extract [37,38], Polygala tenuifolia Root Extract [13], and Terminalia chebula Fruit Extract (in Nutricog®) [39].*

Caffeine also plays a role in this stack due to its antagonism of adenosine receptors. Since adenosine receptor activation reduces dopaminergic activity, supporting the optimal activity of adenosine receptors can indirectly contribute to enhanced dopaminergic signaling [20,21,40].*

Glutamate Signaling and Synaptic Plasticity

Glutamate is the main excitatory neurotransmitter in our brain and central nervous system (CNS) [an excitatory neurotransmitter increases the likelihood that the neuron it acts upon will fire an action potential (also called a nerve impulse); the opposite is called an inhibitory neurotransmitter]. Because it is the main molecule promoting neuronal excitation, glutamate is the principal mediator of cognition, emotions, sensory information, and motor coordination and is linked to the activity of most other neurotransmitter systems. But glutamate is not a “more is better” molecule. Glutamatergic communication requires that the right concentrations of glutamate be released in the right places for only small amounts of time. Less than this results in poor communication. More than this can be neurotoxic and can damage neurons and neural networks.

Therefore, the most important design factor for a glutamate signaling stack is to promote receptor sensitivity to glutamate while avoiding excessive glutamate signaling. Other considerations are the support of (1) enzyme function involved in glutamate synthesis, signaling, and cleanup; and (2) endogenous neuroprotective systems.*

Glutamate does not cross the blood-brain barrier and must be synthesized in neurons from precursor molecules that can get into the brain. In the brain, the amino acid glutamine is the fundamental building block for glutamate. The most prevalent biosynthetic pathway synthesizes glutamate from glutamine using an enzyme called glutaminase. Glutamate can also be produced from an intermediate of the citric acid cycle (also called the Krebs cycle, a central pathway of cell energy metabolism) called α-ketoglutarate (α-KG) by an enzyme called glutamate dehydrogenase, which requires NAD+ as cofactor. Because NAD+ is the coenzyme form of vitamin B3, Niacinamide has been included to support this coenzyme function.* This same enzyme can reconvert glutamate back into α-KG, meaning that, because of this enzyme, glutamate and α-KG can be continuously converted into each other. This dynamic equilibrium is a key intersection between anabolic and catabolic pathways and allows the body to shift resources in whichever direction is required.

There are two general types of glutamate receptors. One type are called ionotropic receptors: glutamate binding to these receptors allows the entry of ions (i.e., electrically charged minerals such as sodium or calcium) into the cell. There are three classes of ionotropic glutamate receptors: (1) N-methyl-D-aspartate (NMDA), (2) α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and (3) kainate receptors. The second type of receptors are linked to molecules that activate intracellular signaling pathways after glutamate binding. These are called G protein-coupled or metabotropic receptors. Metabotropic glutamate receptors (mGluR) modulate synaptic transmission (i.e. neuronal communication) by regulating the activity of a wide variety of ion channels, including ionotropic glutamate receptors, as well as receptors for other neurotransmitters. Carnitine (from Acetyl-L-Carnitine) might support and protect metabotropic glutamate receptors [41].* 

Glutamate and its receptors, particularly NMDA and AMPA, are central elements in memory formation and retrieval because of their role in the key cellular mechanism of memory and learning called long-term potentiation (LTP) [42]. LTP is a form of synaptic plasticity, a term that refers to the biochemical processes through which synapses respond to patterns of activity, either by strengthening in response to increased activity or by weakening in response to decreased activity. LTP is the persistent strengthening component of plasticity and one of the major cellular mechanisms that underlies how the brain encodes memories. Acetylcholine’s effect on memory is also associated with LTP as cholinergic projections to the hippocampus can modulate glutamatergic signaling and LTP [43]. Taurine [44], Saffron Stigma Extract  [45], Polygala tenuifolia Root Extract  [14,46], and Lion’s Mane Mushroom (as RealLionsMane™) [47]. have been shown to support LTP and synaptic plasticity.*

However, excessive glutamatergic activity can be toxic, an effect known as glutamate excitotoxicity. This effect is due to an excessive entry of calcium ions into the cell, which can trigger cell-damaging pathways. Therefore, it is important that the enhancement of glutamate signaling is supported in a way that avoids such effects while at the same time allowing LTP to occur. This approach to neuroprotection is achieved by avoiding excessive activation of NMDA receptors, while leaving normal function relatively intact, thereby optimizing a balanced calcium influx [48].*

Magnesium plays a key role in supporting the regulation of NMDA receptor excitability. At a resting membrane potential (i.e., pre-glutamate excitation), Mg2+ ions act to block the ion channel of NMDA receptors. Glutamate excitation relieves the Mg2+ blockade, which allows calcium (Ca2+) influx through NMDA receptors. Low levels of Mg2+ in the CNS (i.e., a relative magnesium insufficiency) contribute to the hyperexcitability of NMDA receptors. As a consequence, fewer NMDA channels will be blocked, more NMDA channels will be opened at lower membrane potentials, and an excessive calcium influx can occur at a lower threshold of glutamate signaling, leading to excitotoxicity. Neuronal Mg2+ and Ca2+ concentrations are therefore of major neurophysiological importance. Because magnesium modulates calcium entry into cells, Magnesium was included to support balanced calcium signaling* [49,50]. 

We included several other ingredients that have been shown to help regulate NMDA receptor activity, promote balanced glutamate signaling, and/or help to protect neurons from glutamate-induced excitoxicity: Celastrus paniculatus Seed Extract (as SmartSeed™) [51,52], Lion’s Mane Mushroom (as RealLionsMane™) [47], Ginkgo biloba Leaf Extract [53,54], Rhodiola rosea Root Extract [55], Vitamin C [56], Pyrroloquinoline Quinone (PQQ) [57], Taurine [58], and Phosphatidylserine [59].* 

Adaptogenic Support and Stress Resilience

Resilience can be thought of as a generalized capability to cope with emergent challenges or stress. This is the “adaptive” part of the science of complex adaptive systems. The body follows a type of response called hormesis when responding to certain challenges. A hormetic response implies too little or too much exposure results in a suboptimal response, while a just-right range of exposure—the hormetic zone—results in a generally favorable biological response. Exercise follows this type of response. A range of exercise amounts will produce improved fitness and resilience, but below this amount (e.g., sedentary behavior) or above (e.g., injury, overtraining) won’t. Several ingredients, including herbal adaptogens, were included in this formulation due to their resilience-enhancing effects.* 

Adaptogen is a term used to classify substances that support the body’s resistance to stress when taken in the adequate serving range. These substances typically promote homeostasis, providing a normalizing or stabilizing benefit to physiological processes [60]. In a sense, adaptogens can help toughen us up, by producing a small amount of stress, which in turn allows our body to respond better to other sources of stress.*

A central element to the maintenance of homeostasis is the neuroendocrine system, a set of mechanisms by which the hypothalamus maintains homeostasis. The hypothalamic–pituitary–adrenal (HPA) axis, a complex network of interactions among the hypothalamus, the pituitary gland, and the adrenal gland, is of particular interest due to its role in the regulation of stress responses, mood, and energy storage and expenditure [61].

There are several important molecules whose production is induced by stress and that mediate adaptogenic effects and coordinate the adaptive stress response. These include the stress hormone cortisol, stress-activated protein kinases, and heat shock proteins, for example. These factors, and many more, are part of an innate response to stress. The result of this complex response produces improved tolerance and protection from future stress. It also promotes adaptation via feedback-mediated downregulation of the activated HPA axis [60,62].

Rhodiola rosea is one of the most potent adaptogens.* Its adaptogenic effects have been confirmed in multiple studies. It has shown stress-protective and endocrine-normalizing benefits. It has also been shown to promote healthy mood, cognitive performance, and attention, and to help relieve fatigue in stress-related conditions [63].* Rhodiola rosea Root Extract provides an anti-stress effect by promoting balance of the HPA axis [64].* It has been shown to help modulate the levels of several molecules involved in stress responses, namely cortisol [63,65,66].* 

In addition to Rhodiola, other ingredients also have adaptogenic benefits. Gingko biloba Leaf Extract may help reduce stress and keep stress hormone levels balanced [67]. Polygala tenuifolia Root Extract has been shown to support healthy behavioral and physiological responses to stress [68–70]. Phosphatidylserine promotes balanced levels of adrenocorticotropin and cortisol in response to physical stress [71]. Terminalia chebula Fruit Extract (in Nutricog®) has been shown to help modulate cortisol levels and support healthy behavioral stress responses [39]. Lutein and Zeaxanthin (in Lutemax Brain Marigold Flower Extract) have been shown to support healthy stress responses and emotional health [72].* 

Vitamin B5 is often thought of as an “anti-stress vitamin.” It plays a role in this stack due to its importance in promoting the integrity of the cells of the adrenal cortex [73]. The adrenal glands are part of the HPA axis and are responsible for the synthesis of corticosteroids, which have important roles not only in the stress response, but also in metabolism, immune response, and behavior. Magnesium also supports healthy behavioral and physiological responses to stress and mental well-being [74–79].*

Neurotrophins and Structural Plasticity

Neuroplasticity is the ability of the brain to adapt by changing aspects of its structure and function throughout an individual's life. The generation of new neurons, the preservation of existing ones, and the creation of new connections between them is a set of interrelated processes that greatly contribute to brain function. 

Neurotrophins—nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4)—are a family of growth factors that regulate the development, maintenance, survival, and function of the nervous system. Neurotrophin support is an emphasis of this stack.*

BDNF is of particular relevance. BDNF has been reported to promote neurogenesis, regulate the proliferation of neuronal precursors, and promote the differentiation, maturation, and integration of newborn neurons in the hippocampus. BDNF has also shown marked effects on dendrite and spine development and maturation, increasing dendrite branching, length, and complexity. BDNF is also involved in synaptogenesis (i.e., formation of connections between neurons) and synaptic maturation [80–83]. NGF is another important neurotrophin that is also involved in the proliferation, growth, maintenance, and survival of neurons. It promotes peripheral nerve regeneration and myelin repair [84]. 

Several ingredients in Qualia Mind may support the healthy production and function of BDNF: Lion’s Mane Mushroom (as RealLionsMane™) [85–88], Ginkgo biloba Leaf Extract [89], Taurine [90], L-Theanine [91], Magnesium [78,92,93], Lutein and Zeaxanthin (in Lutemax Brain) [94], Oroxylum indicum bark extract (in Sabroxy®) [95–99], Saffron Stigma Extract [100,101], Polygala tenuifolia Root Extract [46,68] and Terminalia chebula Fruit Extract (in Nutricog®) [102,103] and Boswellia serrata Gum Resin Extract (in Nutricog®) [104,105].* Ingredients that may promote the optimal synthesis or the activity of NGF include Lion’s Mane Mushroom (as RealLionsMane™) [106–108], Pyrroloquinoline quinone (PQQ) [109], and Phosphatidylserine [110].* 

Possibly due to the support of neurotrophic levels, several ingredients have been shown to support healthy neuronal structure and structural plasticity. L-theanine [6] and compounds found in Rhodiola rosea Root Extract [111] and Oroxylum indicum bark extract (in Sabroxy®) [112] supported hippocampal neurogenesis in animals. Magnesium [113] and Polygala tenuifolia Root Extract [114,115] supported the proliferation of neural stem cells. Boswellia serrata Gum Resin Extract (in Nutricog®) has been shown to support hippocampal neuronal structure, namely dendrite length and branching and dendritic spine density [116–119]. Peripheral nerve regeneration has been supported by compounds found in Rhodiola rosea Root Extract [120] and by a combination of Vitamins B1, B6, and B12 [121]. Vitamin D as cholecalciferol (VegD3®) has supported optimal myelination [122], i.e., the production of myelin—a lipid-rich substance that forms a sheath around axons that protects and insulates them and that supports nerve impulse conduction and efficient information transmission.* 

Lion’s Mane Mushroom has supported healthy brain structure and plasticity in several studies [85,88,106,107,123–128].* Lion’s Mane has shown the ability to preserve brain volume in the cerebellum of aged mice [124]. Lion’s Mane also promoted healthy neurogenesis in the cerebellum of aged mice [123], as well as in the hippocampus of non-aged mice [108,128]. Studies in vitro showed that Lion’s Mane promoted the healthy growth of axons and dendrites [88,106] and fostered the maturation of oligodendrocytes, the glial cells of the CNS that produce myelin, and maintained the healthy production of myelin [125,126]. In human studies, Lion’s Mane administration to older individuals with poor cognitive function helped preserve healthy brain structure (white matter) and promoted neural organization [85].*

Cell Membrane Integrity

The cell membrane separates the interior of all cells from the outside environment. It protects the cell from its surroundings, controls the movement of substances in and out of cells, and plays a major role in signaling (i.e., communication between what's inside and outside cells). The cell membrane is made predominantly from specialized fats or lipids.

Our formulation includes several ingredients intended to support membrane health and function because cell membranes, particularly neuronal membranes, are essential for cognitive performance.*

When we discussed the choline signaling stack, the CDP-choline pathway was mentioned. It is half of a bigger pathway known as the Kennedy pathway. The other half of the Kennedy pathway is the CDP-ethanolamine pathway, which produces a different phospholipid end product called phosphatidylethanolamine. A big emphasis of this stack is supporting the Kennedy pathway.*

Phosphatidylserine was included in Qualia Mind because it is an essential component of cell membranes. It accounts for 13–15% of the phospholipids (i.e., specialized fat molecules that make up most of the cell membrane) in the human cerebral cortex. In the plasma membrane, phosphatidylserine is localized in the cytoplasmic layer where it’s part of protein docking sites required for the activation of several important signaling pathways. In synapses, phosphatidylserine has a significant role in modulating neurotransmitter release through exocytosis (i.e., expelling these molecules out of the cell) by influencing calcium-dependent fusion of synaptic vesicles and the plasma membrane [4]. Phosphatidylserine can also be converted to other phospholipids, particularly phosphatidylethanolamine, another important structural fat used in the cell membrane, so supports the second half of the Kennedy pathway.*

Alpha-GPC and CDP-Choline also promote membrane health by supporting the first half of the Kennedy pathway (i.e.,  phosphatidylcholine synthesis). Besides being the major source of choline for the choline pool, phosphatidylcholine is a primary component of cell membranes. Supporting the enhanced production of phosphatidylcholine, along with phosphatidylethanolamine via phosphatidylserine, promotes the structural integrity of cell membranes.*

Antioxidant Defenses and Neuroprotection 

Reactive oxygen species (ROS) are a normal byproduct of healthy metabolism—they are created by the oxidation and reduction (redox) reactions used by mitochondria when ATP is produced. ROS were once thought of as unwanted byproducts of mitochondria energy generation (i.e., the free-radical theory of aging). More recent findings have led to a more nuanced understanding of the roles of ROS, particularly in mitohormesis. This is the mitochondrial equivalent of the hormesis principle, previously mentioned in the Adaptogenic Support and Stress Resilience section. 

Mitohormesis implies that a zone of ROS causes mitochondria to toughen up, build adaptive capacities, and perform better. It also implies that excessive ROS can damage cellular membranes and impair cell energy processes (including ATP generation). The body has evolved a complex system of antioxidant defenses to allow it to adapt to and protect itself from ROS. A molecule called glutathione (and its related enzymes) plays a central role in antioxidant defense. Other antioxidant enzymes, such as catalase and superoxide dismutase, are also critical parts of the overall antioxidant defenses. 

The brain, due to its high metabolic rate, consumes 20% of the total body oxygen, making it a big producer of ROS. Excessive ROS production, and the oxidative damage this can cause, is thought to be one of the main contributing agents to premature brain aging and cognitive decline. Therefore, it’s important that the brain’s antioxidant defense system be supported in ways that allow it to deal efficiently with ROS and maintain redox balance. Several ingredients in this formulation provide benefits in this area, either by acting as antioxidants, by promoting antioxidant defenses, or both.*

Vitamin C as Ascorbic Acid is a potent antioxidant. As an electron donor, it can help oppose and thereby neutralize ROS [129]. Vitamin C is essential for the maintenance of the redox balance of the brain [130].* Lutein and Zeaxanthin (in Lutemax Brain) are carotenoids with potent antioxidant action; they are among the predominant carotenoids in the brain where they support antioxidant defenses [131].* 

Pyrroloquinoline quinone (PQQ) is a redox cofactor that combats oxidants and is continuously recycled into its active form by glutathione [132].* PQQ is 100–1000 times more efficient in redox cycling than other quinone biofactors and is capable of continuously performing repeated oxidation and reduction reactions [133].* Vitamin D as cholecalciferol (VegD3®) also has antioxidant properties, is associated with major plasma redox systems [134], and inhibits lipid peroxidation [135], suggesting that it helps protect healthy cellular membranes (which have a high lipid content) from oxidation. Taurine has multiple antioxidant functions, including supporting glutathione and promoting antioxidant defenses [136].* 

Herbal extracts are sources of phytochemical compounds with potent antioxidant action, such as polyphenols. These compounds can contribute to the support of antioxidant defenses by promoting the production or activity of antioxidant enzymes and other brain detox systems. Several of the herbal extracts included in Qualia Mind have antioxidant properties due to their phytochemical components, including Celastrus paniculatus Seed Extract (as SmartSeed™) [137–139], Rhodiola rosea Root Extract [140], Ginkgo biloba Leaf Extract [141], Polygala tenuifolia Root Extract [13,14,142,143], Oroxylum indicum bark extract (as Sabroxy®) [144–146], Terminalia chebula Fruit Extract (in Nutricog®) [9,103,147–149], Boswellia serrata Gum Resin Extract (in Nutricog®) [105,150–152]), and Saffron Stigma Extract [18,153–155].*

Some phytochemicals can also support healthy immune signaling in the brain, which, along with the support of antioxidant defenses, may promote healthy neuroprotective functions and promote the maintenance of brain health. Neuroprotective functions have been supported by Oroxylum indicum bark extract (Sabroxy®) [96,144–146,156–158], Polygala tenuifolia Root Extract [46,142,159–163], Saffron Stigma Extract [18,31,32,153,164,165], Terminalia chebula Fruit Extract (in Nutricog®) [9,16,103,147–149,166], Boswellia serrata Gum Resin Extract (in Nutricog®) [105,150–152,167,168], L-Theanine [169–173], Ginkgo biloba Leaf Extract [89], and Lion’s Mane Mushroom (as RealLionsMane™) [124,174–176].*

Cerebral Blood Flow 

Optimal cerebral blood flow is of obvious importance, not only because it is fundamental for the proper delivery of oxygen and metabolic ingredients, but also for the removal of waste products of cellular metabolism from the brain. Cerebral blood flow is also fundamental for the delivery of the ingredients included in this formulation. And it’s important to choose compounds and forms of nutrients that can pass into the brain (i.e., gain access through the blood-brain barrier). Some of our ingredients were chosen based on these considerations.*

Nitric oxide (NO) is a biological messenger and signaling molecule. It plays an important role in circulation. NO is used by endothelial cells—cells that line the interior surface of blood and lymph vessels—as a messenger that instructs the smooth muscle surrounding blood vessels to relax, causing the widening of blood vessels (vasodilation) and increasing blood flow. NO is produced by enzymes called nitric oxide synthases (endothelial NOS, eNOS, in this case) in a reaction that requires NADPH (vitamin B3-dependent). This stack includes two ingredients that can indirectly support NO’s blood flow improving effects: Vitamin C as Ascorbic Acid, which helps promote healthy endothelial NO synthesis [177], and Vitamin B3 as Niacinamide, which is a precursor to NADPH [178].* 

Vitamin C also plays an important role in supporting the synthesis of collagen and elastin [179],* important structural components of blood vessels. Elastin confers elasticity and collagen confers strength, both essential for blood flow and general vascular health. Niacinamide provides blood flow benefits by supportingmicrovascular density and microcirculation [180,181].* Further support for healthy blood flow may be provided by Terminalia chebula Fruit Extract [166,182,183] and Boswellia serrata Gum Resin Extract [184,185] (both in Nutricog®) by supporting endothelial cell function. Ginkgo biloba Leaf Extract has several active compounds that promote healthy circulation, clot formation, capillaries, and help protect nerve cells from low oxygen conditions, thereby promoting healthy cerebral blood flow [186].* Taurine has also been shown to support healthy cerebral blood flow* [187].

Cell Energy and Metabolism 

The body’s (and brain’s) "energy currency" is called adenosine triphosphate (ATP). Most ATP is produced in specialized structures within cells called mitochondria. A central set of reactions involved in ATP production are collectively known as the citric acid cycle, or Krebs cycle. Given the brain’s high metabolic rate, it is a big user of this energy currency. 

The overall ATP production process is called aerobic respiration. This process starts with the generation of pyruvate from the simple sugar glucose—a process called glycolysis—in the liquid found inside cells (i.e., cytosol). The pyruvate is then transported into mitochondria, where it is converted into acetyl-CoA. Acetyl-CoA is a pivotal molecule in cellular metabolism because it donates the main substrate of the citric acid cycle, the acetyl group. In the citric acid cycle, a series of chemical reactions transfer electrons to NAD+ and FAD, which in turn transfer them to the electron transport chain to power ATP production, in a process known as oxidative phosphorylation [188].

B vitamins play a key role in many steps during the ATP production process [189]. Because B vitamins are involved in the different interrelated pathways of energy generation, deficiency or inadequacy in any of the B vitamins can have a negative impact on the whole process (i.e., cell energy production suffers). We included all B complex vitamins because of the major roles they play.* 

Vitamin B1 as Thiamine HCL (used in the mitochondrial pyruvate dehydrogenase complex as an example), Vitamin B2 as Riboflavin (needed to produce FAD), and Vitamin B3 (needed to produce NAD+) are essential in mitochondrial aerobic respiration due to their roles as coenzymes in the citric acid cycle and the electron transport chain, and consequently, in the production of ATP [188].* 

Vitamin B12, as Methylcobalamin, is a coenzyme form of cobalamin needed for the activity of the methionine synthase enzyme. Methionine synthase plays an important role in cellular metabolic processes associated with the transfer of methyl groups (one-carbon metabolism). In the methionine synthase reaction, Methylcobalamin accepts and donates a methyl group. This allows for the conversion of L-5'-Methyltetrahydrofolate (an active form of Folate / Vitamin B9) and homocysteine into tetrahydrofolate and methionine. Methionine is then further metabolized into S-adenosylmethionine (SAMe), a universal methyl donor. Because of their roles in one-carbon metabolism, L-5'-Methyltetrahydrofolate and Methylcobalamin sit at the crossroads of a pathway that impacts the synthesis of many metabolically important compounds, including nucleic acids and amino acids [188].*

Vitamin B6 in its active form of Pyridoxal-5′-Phosphate is a coenzyme in many metabolic pathways important for cellular energy generation, including glycogen (a complex sugar) breakdown and amino acid metabolism [188]. Biotin (Vitamin B7) is an important cofactor in some enzymes involved in the metabolism of carbohydrates, fats, and amino acids  [190].*

Besides being a central molecule in metabolism and energy production, acetyl-CoA is also involved in many other enzymatic processes. Acetyl-CoA is estimated to be a cofactor for about 4% of all known enzymes [73]. The addition of Vitamin B5 as Calcium Pantothenate to this stack is therefore meant to support cellular energy production by providing supplemental amounts of the precursor to Acetyl-CoA and to augment the performance of enzymes at a more system-wide level. The inclusion of Acetyl-L-Carnitine and N-Acetyl-Tyrosine provides acetyl groups to help augment the acetyl pool for the synthesis of acetyl-CoA.* 

After donating its acetyl group, N-Acetyl-Tyrosine yields the amino acid L-tyrosine, a building block for proteins and neurotransmitters. Acetyl-L-Carnitine can be  converted into carnitine, which plays a key role in the transport of long-chain fatty acids into mitochondria for ATP generation. Vitamin C contributes to healthy carnitine levels because it is a cofactor in two enzymes that are necessary for its synthesis [191].*

Pyrroloquinoline quinone (PQQ) has an important role in supporting cellular energy generation, primarily via its action on mitochondria. PQQ has been linked to supporting the activation and expression of molecules with important roles in cellular energy metabolism and mitochondrial biogenesis (process cells use to produce more mitochondria to support greater ATP production) [192,193]. Prolonged PQQ intake has been shown to support healthy mitochondrial biogenesis and mitochondria efficiency [193,194].* 

Magnesium is required for the activity of all enzymes that use and many that synthesize ATP. In the brain, like in all other organs, magnesium supports healthy mitochondrial function and is involved in all biochemical and metabolic pathways essential for cellular energy metabolism [195,196].* 

Vision and Hearing

The visual system is the largest system in the brain. Poor visual quality and reduced visual health are linked to poorer cognitive function and an accelerated age-related deterioration of cognitive performance [197–206]. Conversely, better visual acuity was found to be correlated with better cognitive function [207,208], including in later life [198].

Currently, one of the main factors contributing to the deterioration of visual health is blue light emitted by screens. Blue light promotes an excessive generation of reactive oxygen species (ROS) in the retina that can be stressful to retinal function by inducing oxidative stress [209]. The central zone of the retina—called macula—is the area where the lens focuses light to generate sharp images, and therefore also the area of the retina most intensely exposed to light energy and thus most susceptible to blue light stress. 

To protect the fovea from light stress, macular pigments (or macular carotenoids)—lutein, zeaxanthin, and meso-zeaxanthin—absorb excess blue light, acting a bit like shade or blue-blockers for the retina, and thereby conferring protection to this area where light is focused and light energy is most intense [210–213]. Therefore, macular pigments have a key role in supporting the many functions important to eye health and visual performance [214–218]. Lutein and Zeaxanthin must be obtained from the diet. After we consume them, they accumulate in the macula; meso-zeaxanthin can be produced in the retina from lutein [214]. Therefore, adequate dietary levels of macular pigments are essential for a healthy visual response to blue light.* 

Supplementation with lutein, zeaxanthin, and meso-zeaxanthin supports macular pigment levels [219] and has been shown to support retinal and visual function and resistance to photostress, eye strain, and visual fatigue [220–235]. This is one of the main reasons why we included in Qualia Mind Lutein, Zeaxanthin, and Meso-Zeaxanthin as Lutemax Brain Marigold Flower Extract to support visual health and cognition [131,218,236–238].* 

Saffron Stigma Extract is also loaded with healthy bioactive compounds, including eye-healthy carotenoids. Saffron supports antioxidant defenses in the eye [154,155,239], macular health [240–242], healthy retinal function [32,154,155,239–244], and retinal responses to intense light [239,245–247], important for screen stress resistance. Saffron also supports healthy visual acuity [240,242].*

Vitamin B12 as Methylcobalamin provides essential support for healthy nerves. The eye has many important nerves whose function may be supported by methylcobalamin, particularly the optic nerve, which carries visual information to the brain [248–257]. Methylcobalamin supports healthy visual function when using devices with screens [258,259].* Pyrroloquinoline Quinone (PQQ) supported protection against noise-induced and age-related hearing loss in mice [260].*

Taurine is the most abundant amino acid in the retina (as well as other parts of the eye like the lens and cornea). The majority of the taurine pool of the retina is in photoreceptors, where taurine is essential for their light-capturing function, acts as an antioxidant, and supports protection against stress from blue light and ultraviolet light [261–267]. Through these actions, Taurine supports resistance to visual fatigue [268].*

Qualia Mind also provides support for healthy hearing, which like vision, is essential for maintaining cognitive health [269]. Taurine is found in the cochlea, the part of the inner ear involved in hearing [270,271]. It has been shown to support auditory neurons [272–274], neuroprotective functions in the cochlea [275], and auditory health in animal studies [276].* Qualia Mind also includes magnesium as Magnesium Aspartate, a form that has been used in several clinical studies to support healthy hearing and noise protection [277–283]*

Qualia Mind: Comprehensive Support of Cognitive Performance 

At Qualia we believe that one of the most exciting properties of nootropics is their complementarity. Selecting and combining different brain ingredients into nootropic stacks based on knowledge about neurophysiology and neurobiology and the mechanisms of action of each compound allows for many different targeted interventions in the brain. Every possible mechanism of action is relevant and helpful on its own, but when we bring them together to support different aspects of brain health, structure, and function, we get a more comprehensive and sustained support of cognitive performance—a whole system upgrade.*

By supporting balanced neurotransmitter levels and synaptic plasticity, Qualia Mind may contribute to promoting healthy memory, learning, executive function, and motivation. And by adding adaptogenic support, Qualia Mind may even help to promote healthy mood and stress regulation, allowing you to perform well even in demanding or stressful situations.* 

By supporting neurotrophins, healthy brain structure, cell membrane integrity, antioxidant defenses, and neuroprotective functions, Qualia Mind may help to maintain brain health and a neuronal environment that allows neurons and other cells to carry out their function efficiently.* 

By supporting healthy blood flow and metabolism, Qualia Mind may help to circulate the nutrients the brain needs to generate energy to sustain attention, maintain focus, and process information, while also helping to maintain mental energy and alleviate mental fatigue. *

Together, these mechanisms of action help support the brain’s capacity to efficiently execute even the most complex cognitive tasks, such as reasoning, abstract thinking, and creativity.* 

*These statements have not been evaluated by the Food and Drug Administration (FDA). This product is not intended to diagnose, treat, cure, or prevent any disease.

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