STRESS & ANXIETY: Underlying Factors That Generate Neurodegenerative Conditions

TOP 10 NUTRACEUTICAL TARGETING AGENTS

To Modulate Runaway Neurotransmitter Responses

The number of lives affected by stress and anxiety is currently the highest in U.S. history and can ultimately be a source of major physical and mental debilitation for many Americans. Although many factors can play a direct role in the initiation of stress and anxiety, understanding the neurobiological networks and how they are compromised is critical when devising a health program and recommending nutritional supplements for your clients.

The imbalance of the neurotransmitters serotonin, dopamine, norepinephrine, and gamma-aminobutyric acid (GABA) are specifically thought to be linked to mood and anxiety disorders:

► Serotonin assists in keeping us emotionally stable, and our sleep and eating patterns consistent.

► Dopamine allows us to feel pleasure, process feelings, and care for others.

► Norepinephrine gives us the ability to be aroused and to have energy and drive. It controls our “fight or flight” instincts. 

► GABA helps us control anxiety, impulses, and helps us maintain a balanced thought process.

According to market experts, the biggest deterrent to patients purchasing a nutritional supplement is the lack of confidence that it can support their health needs. What is important to understand is there is no “silver bullet” dietary supplement that is going to take away all their stress and anxiety. Nutrition cannot be used in this allopathic manner.

The Excitotoxic Neurotransmitter Process

In his summary article, “The Overlooked Role of Chronic Infection in Neurodegeneration and Its Reversal Using Nutraceutical Agents”, Dr. Robert J. Marshall, PhD, identified the devastating, runaway free-radical, neurotransmitter phenomena that is responsible for the creation of high levels of stress and anxiety in many cultures today and their long-term effects that are able to initiate neurodegeneration conditions.

The excitotoxic neurotransmitter process often begins at the cellular level through two main processes which act relentlessly to excite the cell until it weakens to the point of apoptosis. The two devastating forces at the cellular level are: a) free radicals formed by the reactive oxygen species and those of reactive nitrogen species, and b) excitotoxins, such as glutamate (monosodium glutamate or MSG), aspartate (i.e. NutraSweet) and homocysteine. Excitotoxins are neurotransmitters which can cause feelings of stress and anxiety but they also yield low cell energy or even cell death when their actions are prolonged.

When the mitochondrial energy drops to low levels, the cell’s sensitivity to excitotoxicity is greatly increased so that even normally occurring amounts of neurotransmitters, such as glutamate, may create a hyperactive neurotransmitter response at the NMDA (N-methyl-D-aspartate) pathway, adversely affecting healthy mood and relaxation responses. As a consequence, this puts the cell into a tailspin, generating further free radical pathology from overstimulated excitotoxic neurotransmitters, until eventually the cell’s P-53 gene encoding is activated to destroy itself—creating a neurodegenerative response and progression.

Artificial Electromagnetic Fields: Their Devastating Role In Stress, Anxiety And Neurodegeneration

Dr. Martin Pall published extensive evidence in his landmark article, “Electromagnetic fields act via activation of voltage-gated calcium channels to produce beneficial or adverse effects”, where he clearly demonstrates that EMF exposure can act to produce excessive activity of Voltage-Gated Calcium Channel (VGCCs) in many cell types, suggesting that these may be direct targets of EMF exposure.1

Voltage-gated calcium channel stimulation further stresses this neurotransmitter process at the NMDA pathway. Increased intracellular Ca2+ can act in turn to stimulate the two calcium/calmodulin-dependent nitric oxide synthases and thus, increase nitric oxide.1 The increased intracellular Ca2+ produced by such VGCC activation may lead to multiple regulatory responses, including the increased nitric oxide levels produced through the action of the two Ca2+/calmodulin-dependent nitric oxide synthases, nNOS and eNOS. Increased nitric oxide levels typically act in a physiological context through increased synthesis of cGMP and subsequent activation of protein kinase G. In contrast, in most pathophysiological contexts, nitric oxide reacts with superoxide to form peroxynitrite, a potent oxidant which can produce radical products, including the hydroxyl radical and NO2 radical.1

Peroxynitrite has been shown to produce single-strand DNA breaks, a process that is inhibited by many but not all antioxidants. The data on the generation of single-strand DNA breaks, although quite limited, supports a mechanism that involves nitric oxide/peroxynitrite/free radical (oxidative stress) damage.1

The peroxyl radical can lead to neuron, membrane and mitochondrial damage. It can result from calcium excess with low magnesium levels at the neuron and can lead to the production of protein kinase C2 which in turn, can increase inflammatory arachidonic acid levels.

Another result of free radical activity is lipid peroxidation which can yield the toxic compound, 4-hydroxynonenal, the most protein reactive product of lipid peroxidation. These compounds can increase the neurofibrillary tangles as seen in Alzheimer’s disease. In every cell of the body, both the cell nucleus and the mitochondrial DNA are vulnerable to free radical damage. However, mitochondrial DNA is 10 times more sensitive to free radical damage. This extreme vulnerability of mitochondrial DNA to free radical damage can be elegantly protected by targeted nutraceutical agents.

When mitochondrial DNA is oxidized, cellular energy is reduced and the cell’s sensitivity to excitotoxicity is greatly increased so that even normally occurring amounts of neurotransmitters, such as glutamate, can cause stress and some cells or trigger cell death for others.

1“Electromagnetic fields act via activation of voltage‐gated calcium channels to produce beneficial or adverse effects”, Martin L. Pall First published: 26 June 2013 https://doi.org/10.1111/jcmm.12088

Top 10 Nutraceutical Agents

To eliminate overactive stress and anxiety responses, the goal is to promote healthy neurotransmitter responses that can help support the body to reconnect its neural circuitries and promote healthy mood and mental health during times of stress.

Understanding this process and educating your clients with science-based information will help them make intelligent decisions. Investing time in your client beyond the sale of a supplement, including nutraceutical, dietary, and lifestyle information, may mean the difference between your client being able to continue a good quality of life or surrendering their mental health and emotional wellbeing to a devastating state of sadness and hopelessness.

Consuming a substandard diet that is deficient in nutrient intake, especially lacking key, baseline nutrients such as minerals, vitamins, antioxidants and essential fatty acids, can directly lead to an imbalance of neurotransmitters. As a consequence, feelings of chronic stress and anxiety are rampant. 

Instead, following a nutrient-dense dietary plan in addition to adopting a well-designed “Stress and Anxiety” nutritional supplement program with targeted nutraceutical agents (see below) can be a powerful strategy for a client who is seeking to promote a healthy neurotransmitter balance to support their mood and emotional wellbeing that can forever transform their lives.

1. Hemp Extract (Full Spectrum)

The ECS Stabilizer

The endocannabinoid system (ECS) promotes biological stability by acting as the master conductor orchestrating the activities of the central nervous system, synaptic plasticity, and responses to endogenous and environmental insults. The ECS is known to influence neuroplasticity, cellular and neuronal activity, neuroinflammation, and cerebrovascular activity.

Full spectrum hemp extract promotes ECS balance and may help with:

Maintaining healthy neuromodulation—which is attributed to potential neuroprotective properties for the CNS. CB1 receptor activation results in the inhibition of adenylyl cyclase and blockade of voltage-operated calcium channels which decreases neurotransmitter release, thus suppressing neuronal excitability and inhibiting neurotransmission. These effects have led to the study of phytocannabinoids for neuromodulatory activity such as increasing adenosine levels by reducing adenosine reuptake for neuroprotection benefits. This effect is potentially attributed to CB1 and/or CB2 receptors that have cannabinoid receptor independent actions, TRP channels, PPARα, etc.*

Relieving mild mood changes and occasional acute stress—which is potentially attributed to CB1 receptors (located in the brain and CNS) and 5-HT-like agonist or serotonin mediation.*

Relieving occasional sleeplessness—which is potentially attributed to CB1 receptors (located in the brain and CNS).*

Antioxidant support—which is potentially attributed to CB2 receptors and/ or cannabinoid receptor independent actions. CBD has been shown to have neuroprotective (antioxidant) benefits by acting as an ROS scavenger, NO synthase protein and (NF)-κB inhibitor and also offers reduction of lipid peroxidation.*

Hemp extract’s nutrient content and phytochemical properties can vary dramatically depending on its growing and harvesting methods and production processes. Many sources of hemp may be poorly grown or contaminated with added synthetic cannabinoids. As a result, substandard hemp products may not offer the full spectrum of benefits that are typically cited in scientific literature. Therefore, how a plant is grown, then processed, is of critical importance.

2. Saffron

Full Spectrum Carotenoids

Saffron extract contains more than 150 naturally occurring compounds that include carotenoids (e.g. crocetin and crocins as glycosidic derivatives), safromotivines, monoterpene aldehydes, safranal and picrocrocin. 

The full spectrum of active, naturally occurring compounds provided by saffron, such as safromotivines, may modulate the levels of both excitatory and inhibitory neurotransmitters by:

► Modulating glutamate release 

► Maintaining dopamine levels 

► Promoting serotonin levels

The carotenoid, crocetin, may promote complementary effects on mood parameters by modulating 5-HT receptor sites that bind to serotonin and mediate excitatory neurotransmission. The 5-HT2C receptor is a subtype of 5-HT receptors which binds serotonin and inhibits dopamine and norepinephrine release in the brain. 5-HT2C receptors are believed to significantly regulate mood, anxiety, feeding and reproductive behavior.

Overactivity of 5-HT2C receptors may contribute to anxiety symptoms in certain types of patients. 5-HT2C receptors act as modulators of the HPA axis (known for the “fight or flight” sympathetic stress response) because serotonin is involved in the basal and stress-induced regulation of the hypothalamus and pituitary gland hormones (including prolactin, ACTH, vasopressin and oxytocin). Active phytochemical agents in saffron, such as crocetin, may hold great promise to help support proper activity of the 5-HT receptors.

3. L-Theanine: Neurotrophic Brain Support

L-theanine (r-glutamylethylamide) is a non-protein amino acid that is not required by the diet to support life. It is referred to as a sedative amino acid and is mostly associated with green tea leaves.

Research shows that L-theanine increases dopamine, GABA, and glycine levels in various areas of the brain, as well as BDNF (brain-derived neurotrophic factor) and NGF (nerve growth factor) levels in certain brain areas. 

L-theanine is structurally similar to GABA and the excitatory neurotransmitter glutamate, and in accordance, binds to glutamate receptors blocking the reuptake of glutamine and glutamate modulating excitotoxicity.

4. Magnolia Bark Extract (Magnolia officinalis)

Neurotransmitter Support

The bark of Magnolia officinalis is well documented in Chinese and Japanese traditions to support healthy anxiety levels during times of stress. Over 250 constituents have been isolated from Magnolia bark but it is the phenolic compounds, magnolol and honokiol, that are the main active constituents.

Both magnolol and honokiol promote the neurotransmitter acetylcholine and appear to be able to modulate GABA benzodiazepine binding sites. Both compounds appear to be anti-glutaminergic. 

Honokiol was shown to be able to prevent NMDA (N-methyl-D-aspartate)-induced Ca2+ influx into neurons while magnolol more generally prevented Ca2+ influx by NMDA receptors and other functions.

5. Rhodiola

The Adaptogenic Golden Root

Rhodiola, also known as Golden root, is a hardy Siberian plant that has been used traditionally for hundreds of years as an adaptogenic botanical agent. Extensive research has shown that Rhodiola offers a range of valuable properties including support for occasional mental and physical stress as well as cardiovascular and metabolic health.

The phytochemistry of Rhodiola is complex and includes a large number of active compounds, such as flavonoids, monoterpernes, phenylpropanoids, triterpenes, phenolic acids, and phenylethanol derivatives. Its neurobiological effects appear to be serotonergic and may promote healthy serotonin and dopamine levels in the brain, thus promoting healthy brain chemistry.

6. EPA/DHA

Brain/Nerve Integrity

The Standard American Diet (SAD) simply does not provide adequate amounts of DHA (docosahexaenoic acid) for the maintenance and development of healthy brain and nerve tissue for the majority of Americans. On average, the typical American diet contains less than 100 mg of DHA per day, well below the amount recommended by several expert organizations around the world.

Worst yet, most Americans continue to consume too much fried food and foods with trans fatty acids (especially hidden in foods when eating out) which are known to inhibit desaturase enzymes that are necessary for the manufacture of life-essential DHA fatty acids found in all cellular membranes throughout the body. 

Taking a quality DHA supplement daily can mean a quantum difference for many people in supporting the health of the brain, nerve, eye, heart etc.—in short, promoting their best quality of life.

Docosahexaenoic acid (DHA) is a critical, polyunsaturated omega-3 fatty acid (PUFA) located in all cellular membranes of the body but are the most abundant in the brain, eyes and heart. It is a major structural fat found in the brain and eye, accounting for up to 97% of the total omega-3 fats in the brain and up to 93% of the omega-3 fats in the retina of the eye. 

DHA is required for maintenance of proper brain function in adults and is essential for the growth and development of the brain in infants. DHA provides structure to nerve cells and helps ensure proper neurotransmission. EPA may be more important in the signaling within nerve cells normalizing communications.

Numerous research studies confirm that all individuals, from infants to the elderly, can benefit from a regular intake of dietary DHA. Just as calcium is essential for building strong bones, DHA helps ensure that the cells in the brain, eyes, heart and other parts of the nervous system develop and function properly throughout all stages of life.

7. B Vitamins

Activated Nerve Support

The vitamin B complex plays an important role in nearly all of the body’s functional systems. Some of the wide-reaching, supportive roles of B vitamins include promoting the health of the nervous system, supporting liver function, promoting skin and hair health as well as maintaining muscle tone in the gastrointestinal tract.

Sufficient B vitamin intake is essential for maintaining adequate energy metabolism, mood balance, hormone synthesis, hemoglobin formation and proper nerve cell impulse transmissions. B vitamins are also vital in promoting healthy neurotransmitter responses.

For example, vitamin B5 promotes the active function of the neurotransmitter acetylcholine; vitamin B6 helps convert the amino acid tryptophan into serotonin; and vitamin B12 is involved in the production of neurotransmitters. When sufficient B vitamin amounts are available, it has a positive effect on regulating many diverse biochemical reactions throughout the body, including cardiovascular, neurological, reproductive and detoxification systems. 

When the diet is deficient in biologically available B vitamins such as vitamin B12 (as methylcobalimin), folate (as 5-methyltetrahydrofolate) and vitamin B6 (as pyridoxal-5-phosphate), then homocysteine metabolism (which enables S-adenosylmethionine (SAMe) synthesis) may be compromised.

Elevated homocysteine levels can be generated due to a toxic or nutritionally deficient diet. When homocysteine levels are increased in the blood, a runaway neurotransmitter response can occur that may escalate into chronic stress and anxiety. Elevated homocysteine levels have been shown to make symptoms of stress and anxiety worse. The toxic metabolic breakdown components of homocysteine metabolism alter the NMDA (N-methyl-D-aspartate) receptor sites and create a degraded pathway that acts as powerful excitotoxic stress that leads to multiple, unwanted negative effects: the generation of peroxynitrite, 4-HNE, hydroxyl and peroxyl radicals that become the drivers for a runaway neurotransmitter excitotoxic response.

To promote ideal homocysteine regulation, B vitamin support is essential and should contain the fully active coenzyme forms of B vitamins, the forms that normally circulate in the blood, such as folate (as 5-methytetrahydrofolate), vitamin B12 (as methylcobalamin) and vitamin B6 (as pyridoxal-5-phosphate). While the body is able to absorb food-source B vitamins, it must further convert them to the coenzyme forms in order for it to become metabolically active in the body.

Unfortunately, over half of the U.S. population is unable to metabolize the unmethylated forms of specific B vitamins, including folate and vitamin B12. When B vitamins are provided to the body in their active biological forms, such as folate (as 5-methyltetrahydrofolate) and vitamin B12 (as methylcobalamin), they are much more bioavailable and have greater tissue retention which can promote the body’s optimal neurotransmitter modulation.

8. Magnesium

The Forgotten Essential Macromineral

Magnesium is an essential macromineral in human diets with a massive number of physiological factors in the human body. In fact, magnesium functions as a cofactor in more than 300 enzymatic reactions. Magnesium is required as a coenzyme to convert tryptophan to serotonin, a neurotransmitter recognized as a major determinant of mental health and mood. 

Magnesium’s biochemical reactions with N-methyl-D-aspartate (NMDA) may modulate glutamates and their potential excitatory neurological transmissions, thus promoting healthy mood and emotions while supporting a relaxant effect and facilitating sleep.

9. CoQ-10 / Antioxidants

Elegant Neurotransmitter Modulators

In the cell, when mitochondrial energy is lowered (such as exposure to MSG), the cell’s sensitivity rises and the probability of an excitotoxic event is greatly increased. This can mean that even when normal amounts of neurotransmitters are present in the cell, such as glutamate, that an excitotoxic effect may be created. This process puts the cell into a tailspin, generating further free radical pathology. As a result of this runaway neurotransmitter response, more free radicals are generated until eventually the cell’s P-53 gene is activated and the cell destroys itself.

The extreme vulnerability of the mitochondrial DNA to free radical stress can be rapidly decreased by the use of CoQ-10. CoQ10 is able to modulate neurotransmitter activity by maintaining healthy levels of nerve growth factor and by supporting the functions of synaptic and intracellular neuronal responses. Through the synaptic NMDA (N-methyl D-aspartate) pathway, CoQ-10 is able to modulate/dampen the excitatory activity of glutamate, thus acting to maintain healthy neurotransmitter activity and support healthy mood during times of stress.

10. Vitamin D3

Full Body Mood and Brain Support

The necessity of vitamin D3 for optimal human health is well known. Its biochemistry underlies many important processes in human nutrition. Vitamin D3 supports an important role in mood regulation by supporting brain and nerve health. Research demonstrates adequate vitamin D levels may significantly promote healthy mood and emotional wellbeing.

Because vitamin D is biosynthetic precursor of numerous molecules, its effects are important for diverse structural and functional purposes in the brain. Sufficient dietary intake of vitamin D3 is critical for tissues and organs whose viability depend on it. Scientific research has shown that adequate vitamin D3 levels are critical to optimal body and brain functioning. Even under ideal conditions, the body may not be able to produce sufficient amounts of vitamin D so vitamin D supplementation is highly recommended.

Other Considerations…

The Glycation-Free Diet

It is well known that diet can have a profound effect on mental health. In the U.S., it is difficult to obtain common fruits, such as grapes and strawberries, that are free of pesticide and chemical residues, even when organically grown. These two fruits often have significant pesticide/chemical residues and in particular, should not be consumed unless obtained from known, chemical-free sources.

Another common source of contamination in fruits and vegetables is the use of tap water to irrigate crops, which often contains pesticide and chemical residues. Even if a crop is grown organically, unless the water supply is purified or clean well water is used, the final harvest can still contain these neurotoxins.

Regular consumption of pesticides, food additives (such as monosodium glutamate [MSG]), food dyes, sugars, especially fructose can lead to runaway excitotoxic effects that stress key neurotransmitters critical to mental health. For example, high dietary intake of simple sugars, especially fructose, can lead to glycation of numerous proteins in cell walls. Glycation is the process of a protein molecule binding to sugar molecules. Once combined with sugar, proteins are significantly more vulnerable to free radical damage which can then form AGEs (advanced glycation end products). AGEs interfere with dopamine utilization. AGEs signal glia cells to overproduce superoxide and nitric oxide. This combination can then produce powerful free radicals, spinning neurotransmitters out of control which negatively affects the mind, mood and emotional wellbeing.

Bonus

Your Microbiome: Its Profound Influence On Stress And Anxiety

Your gut is host to over 40 trillion microorganisms that work in harmony with your body. To put that into perspective, your body has an equivalent amount of human cells as the amount of microorganisms in your gut—it’s like there is a whole person living inside your gut! This community of beneficial bacteria, referred to as the microbiome, is made up of more than 500 different species. Understanding the interactions between our brain and our microbiome has spearheaded a wealth of health and nutrition research as chronic stress and anxiety are reexamined through the lens of the microbiome.

New research demonstrates the microbiome might be one of the most important factors in promoting healthy mood and emotional wellbeing. This is in part due to the fact that 90% of the body’s serotonin is produced by the EC (enterochromaffin) cells that line the digestive tract. The interaction of bacteria with these cells have causal and temporal effects on serotonin production.

Probiotic supplementation clinically supports the microbiome and may significantly promote healthy mood and emotional wellbeing during times of stress. Probiotic supplements (which supply a range of beneficial colonies) may also promote GABA levels—an inhibitory neurotransmitter that is notably involved in regulating excitotoxic processes in various brain regions which modulates healthy mood and behavior.

What makes a probiotic formula truly worthwhile? Here’s what to look for. The key factors below are especially critical when you are evaluating whether a probiotic formula is truly worthwhile:

► The formula contains probiotic bacteria types that are known to be effective.

► The probiotic bacteria are known to remain stable for long periods of time.

► The probiotic bacteria are able to remain alive for long periods of time.

► The probiotic bacteria are capable of reaching the intestines to colonize there.

► The probiotic bacteria are able to thrive and build up their numbers in the intestines.

It is now well known that you are able to beneficially alter the composition of your own gut bacteria by regularly consuming probiotic fermented foods and nutritional supplements.

What Are “Postbiotics”?

“Postbiotics” is a term that refers to the vast array of metabolic byproducts produced from or by probiotic bacteria that have enormous biologic activity in the gut and thus, influence many of your body’s vital functions, including the brain. We now know that these probiotic-produced postbiotic compounds play impressively important roles in regulating and maintaining the body’s healthy internal microbiome. Postbiotic metabolites are the biochemical flux that initiate thousands of chemical reactions in every one of your cells throughout the body.

In humans, fermentation occurs when probiotic bacteria, located throughout the gastrointestinal tract, work to “predigest” the food you eat. This process of fermentation breaks down plant compounds into postbiotic metabolites to release their full nutritional potency. This makes a broad range of natural elements such as vitamins, minerals, and antioxidants exquisitely more bioavailable to the brain.

In his book, “The Mind-Gut Connection”, Dr. E. Meyer points out that the specific host bacteria in your own personal microbiome help transform the food you eat into hundreds of thousands of individual postbiotic metabolites. To keep your microbiome at its healthiest, you must feed it well. Since different bacteria produce different kinds of metabolites, consuming a diversity of different kinds of probiotic bacteria can help create a healthier microbiome.

Feed The Microbiome With Postbiotics – To Feed The Brain

Although a healthy, naturally diverse, intestinal microbiome should be able to produce all the postbiotics that a body needs, regularly consuming the SAD (Standard American Diet) and coming into frequent contact with environmental stressors (which includes exposure to pesticides, antibiotics, chlorine in water, smoking, etc.) can compromise this likelihood and in turn, your vitality may plummet.

A healthy countermeasure is to boost the microbiome with regular doses of high quality, organic fermented foods, such as apple cider vinegar or fermented turmeric. Because fermented foods have been “pre-digested” with a host of probiotic bacteria, they are already in their end-stage form and are capable of naturally delivering a wide variety of highly beneficial postbiotic metabolites to the intestinal microbiome as well as to the brain. Many types of fermented whole foods (such as apples, mushrooms, beets, turmeric, etc.) can all offer a plentiful array of prebiotic, probiotic and postbiotic metabolites.


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Disclaimer

*This information is provided for the use of physicians and other licensed health care practitioners only. This information is intended for physicians and other licensed health care providers to use as a basis for determining whether or not to recommend these products to their patients. This medical and scientific information is not for use by consumers. The dietary supplement products offered by premier research labs are not intended for use by consumers as a means to cure, treat, prevent, diagnose, or mitigate any disease or other medical condition. These statements have not been evaluated by the food and drug administration. These products are not intended to diagnose, treat, cure or prevent any disease.

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