Episode #224: Nitric Oxide with Beth Shirley, RPh, CCN
In a Nutshell
Nitric oxide (NO) is essential for circulation, immune function, hormone balance, brain health, fertility, and preventing clots, with production dropping sharply after age 40 due to diet, stress, medications, genetics (e.g., MTHFR), glyphosate, and post-viral/vax damage; prioritize the safe nitrate-nitrite-NO pathway (via arugula, beets, celery, or oxalate-free supplements like 320mg nitrate capsules) over risky L-arginine/NOS pathway to recouple eNOS, reduce superoxide/oxidative stress, support BH4/methylation, lower blood pressure/inflammation, improve ED/POTS/diabetes/kidney function, and enhance all therapies. Daily dosing: 2 capsules AM + nitrate-rich veggies; test salivary strips to confirm levels; pair with antioxidants like vitamin C/melatonin; avoid mouthwash/antibiotics disrupting oral microbiome conversion. NO deficiency underlies most chronic diseases—optimize as protocol base for microcirculation, mitochondrial ATP, BDNF/neurogenesis, and stem cell efficacy.
These notes were generated by AI and may contain inaccuracies.
Welcome to Better Health Guy Blogcasts, empowering your better health. The content is for informational purposes only and is not intended to diagnose, treat, or cure any illness or medical condition. Nothing in today's discussion is meant to serve as medical advice or as information to facilitate self-treatment. Always discuss health-related decisions with your personal medical authority.
Beth Shirley, RPh, CCN, developed expertise as a compounding pharmacist and board-certified clinical nutritionist over 40 years. Pioneer in integrative pharmacy, junction between traditional pharmacy and clinical use of nutritional supplementation. Since 2009, worked with leading nitric oxide researchers, gaining in-depth knowledge and applications in patient care. Collaborated with scientific community and companies on innovative nutritional ingredients. Formulated product awarded first patent on supplement to increase sexual desire and pleasure. Currently director of education and research for Approved Medical Solutions, distributor of her oxalate-free nitrate product and Libby line of women's wellness products.
Became pharmacist to help people. After 20 years seeing patients return sicker on more drugs, became certified clinical nutritionist in 1997. Known as pharmacist for getting off drugs. Integrative pharmacy near first nitric oxide company, Neo40. Before Neo40 launch, they were clients in 2009. Helped develop L-SEP (likely LSE), released in 2010 as one of first specific nitric oxide products.
Nitric oxide governs circulation and microcirculation, touching every physiological process:
- Cardiovascular: high blood pressure, clotting (critical post-vax/post-viral due to spike protein decimating nitric oxide).
- Learning and memory.
- Kidney health (chronic kidney disease rampant).
- Vision/eyesight (blood vessels need to be open).
- Hormone balance (starts in hypothalamus).
- Immune system (first defense against pathogens).
- Lungs.
- Sex/reproduction (essential for male/female fertility). Nitric oxide has half-life less than a second.
By age 40, eNOS (endothelial nitric oxide synthase) decreases to 50%; by 60, to 15%. Support nitrate-nitrite-nitric oxide pathway. Factors lowering nitric oxide:
- Standard American diet (devoid of nitrate-rich veggies).
- Lack of exercise.
- Medications: antibiotics, azole antifungals, SSRIs, birth control pills, NSAIDs (ibuprofen), PPIs (proton pump inhibitors, originally for 6 weeks, now OTC for decades; interfere with both pathways).
- Pollution, glyphosate, EMF.
- Genetic SNPs: NOS SNPs, MTHFR (interferes with methylation cycle, reducing BH4 tetrahydrobiopterin; BH4 keeps eNOS coupled; uncoupled eNOS produces superoxide).
- Stress (uncouples eNOS, increases oxidative stress).
- Post-viral/post-vax spike protein (causes clots, heart attacks, sudden death, poor thinking due to brain circulation). Black population has more NOS SNPs, predisposed to cardiovascular disease, strokes, heart attacks. More stressors increase demand, depleting supply.
Two pathways: NOS pathway and nitrate-nitrite-nitric oxide pathway. Biohacks (breathing, PEMF) require functioning eNOS or nitrate stores. Nitrate sources: arugula, spinach, beets, celery, bok choy (all high nitrate except arugula may increase oxalates; issue for leaky gut/chronic conditions). Other supports: breathing, humming, mouth taping.
Dietary Nitrates and Myths
Nitrates maligned by non-peer-reviewed 1970s study (later discounted). 1972: nitrates in meats paired with vitamin C or erythorbate to prevent nitrosamines. Vegetables provide far more nitrates than processed meats (not healthy due to other factors like smoking). DASH diet (therapy for hypertension) has 1,200-2,500 mg nitrate/day (e.g., 5 oz spinach = 300-400 mg; 7 oz beets similar).
Celery and celery seed high in nitrates. Celery juice benefits likely from nitrates. "No nitrates/nitrites added" foods use celery seed (adds nitrates, not disclosed). Celery seed supplements support blood pressure, vascular health, inflammation, oxidation, kidneys, antimicrobial (overlaps nitric oxide benefits).
Higher nitric oxide led to better COVID outcomes, faster recovery, less vax damage. Nitrite nasal sprays and N101 lozenges (Dr. Bryan study) kill inhaled pathogens but don't raise systemic NO. Spike protein decimates NO, causing clotting (NO governs platelet activation/aggregation). NO deficiency leads to microclots; cells can't be >2 cells from capillary; impairs oxygen/glucose/nutrient delivery, debris removal, tissue death. Recommendations for COVID/vax: high-dose melatonin, nitrate supplement twice daily (especially if chronic issues, as they cause NO deficiency via oxidative stress uncoupling eNOS to produce superoxide).
MTHFR SNPs impair methylation cycle, reducing BH4 production. BH4 keeps eNOS coupled; deficiency causes NO deficiency. Nitrate pathway supports BH4 via cyclooxygenase. NO supplementation fine for MTHFR (despite some claims otherwise).
NO first defense against viral, bacterial, fungal pathogens; deficiency eases pathogen growth. Stress uncouples iNOS. Nitrate-nitrite-NO safe for autoimmunity (many have oxidative stress/inflammation uncoupling eNOS). Talk at A4M on autoimmunity supporting nitrate pathway. Atherosclerosis autoimmune. Raynaud's autoimmune; circulation impaired; NO support led to notable improvement/resolution in cases.
Do not recommend arginine for NOS pathway (sensitive: needs oxygen, NADPH, FAD, BH4, pH; uncoupled + arginine increases ammonia, urea, ADMA (all-cause mortality), herpetic viruses). Nitrate-nitrite-NO pathway:
- Increases NO directly.
- Nitrate supports NOS (increases BH4 via cyclooxygenase; keeps coupled).
- Downregulates NADPH oxidase (makes superoxide), recouples eNOS/electron transport chain. Supports both pathways without risks.
NOS Inhibitors
Stress, lack of exercise, standard diet, meds (antibiotics, azole antifungals, antidepressants, birth control, NSAIDs, PPIs), genetics. For antibiotics/antifungals, support NO with veggies or standard nitrate dose.
BH4 only for NOS pathway (low BH4 still allows success with nitrate pathway). BH4 essential for serotonin, dopamine, norepinephrine, epinephrine, melatonin. Nitrate supports BH4. Other supports: activated B vitamins for methylation, vitamin C (only molecule reducing BH2 back to BH4; deficiency oxidizes to BH2 uncoupling NOS). No readily accessible BH4 tests (lab possible). Pteridin-4 supports BH4.
Women have better NOS NO production until menopause.
Women produce nitric oxide better through the NOS pathway until menopause, when estrogen's support for NOS function and cardiovascular health diminishes, evening out production. The hypothalamus requires adequate nitric oxide to produce gonadotropin-releasing hormone, which stimulates the pituitary to release LH and FSH, traveling to ovaries and testes to produce estrogen, progesterone, and testosterone. These hormones stimulate NOS production of nitric oxide when NOS is coupled. Prolactin interferes with the NOS pathway; high prolactin occurs in PCOS and infertility, which is a nitric oxide-deficient state. Fertility is nitric oxide-mediated in every facet. Cortisol uncouples the NOS enzyme, but most hormones stimulate nitric oxide production, helping keep us young and healthy.
Everyone has ubiquitous environmental exposure to glyphosate, even those eating organic diets show high levels upon testing, as shared by Dr. Neil Nathan. Glyphosate impacts NOS and nitric oxide production and is toxic, present in air, water, and even organic vegetables via contaminated water. Organic vegetables have less nitrate than conventionally grown ones due to fertilizers like potassium nitrate used in conventional farming, which vegetables take up. Eating organically does not disserve nitric oxide or nitrate goals.
eNOS (endothelial NOS) supports vascular health when functioning well, not necessarily upregulated. iNOS (inducible NOS) upregulates hundreds of times during infection to produce more nitric oxide but uncouples with prolonged inflammation and oxidative stress, producing superoxide instead, worsening oxidative stress and inflammation. Chronically upregulated uncoupled iNOS does not control chronic infections as it fails to produce nitric oxide. nNOS (neuronal NOS) is similarly affected. Uncoupling factors are the same across all NOS types: oxidative stress oxidizes BH4 (tetrahydrobiopterin), which holds the NOS dimer together, leading to nitric oxide deficiency.
Exogenous nitric oxide supplements support eNOS, iNOS, and nNOS. Nitrate downregulates upregulated iNOS and modulates NOS enzymes. In chronic issues with oxidative stress, uncoupled iNOS upregulates superoxide production. For those with chronic health challenges, infections, or oxidative stress, increasing nitric oxide via the L-arginine/NOS pathway may be detrimental; focus on the nitrate pathway instead, which avoids iNOS superoxide issues. High-arginine foods (e.g., peanuts can reactivate herpes) or supplements like protein/collagen powders may detrimentally stimulate NOS if uncoupled. Check ADMA (asymmetric dimethyl arginine) levels; elevation indicates uncoupled NOS, high oxidative stress, low BH4, and insufficient nitrate—reduce arginine intake.
BH4 is required for NOS to generate nitric oxide; low BH4 risks superoxide production. Prioritize nitrate pathway over L-arginine/NOS to minimize risks. Dr. Martin Pall discusses excess nitric oxide creating peroxynitrite, damaging cells and driving inflammation via EMF-induced calcium influx activating calmodulin-dependent NOS, reacting with superoxide. However, studies often measure nitrotyrosine (not peroxynitrite directly) and assume causation; peroxynitrite is short-lived and part of the NO cycle converting to inert nitrate. EMF increases NADPH oxidase and superoxide, uncoupling NOS, contributing to nitric oxide deficiency states like cardiovascular disease and diabetes since the 1960s.
Pair nitric oxide support with antioxidants (e.g., hydrogen water, hydrogen gas) to decrease oxidative stress. Nitrate supports healthy gut bacteria, tight junctions (gut, brain), and downregulates LPS production. NADPH oxidase (sole purpose: superoxide production) is upregulated by EMF, infections, inflammation, IL-6, RAS cycle, iron; nitrate-nitrite-NO pathway downregulates it, preventing theft of NADPH needed for detoxification. Superoxide increases oxidative stress, impairs microcirculation, hinders nutrient delivery, therapy efficacy, and cellular debris cleanup. Superoxide with elevated iron (common in chronic illness, MTHFR SNPs) leads to ferroptosis; nitrate-nitrite-NO downregulates ferroptosis.
Chronic stress and cortisol increase superoxide, decrease nitric oxide by uncoupling NOS, impairing infection fighting, causing cardiovascular disease, strokes, MIs via eNOS uncoupling, and blocking arginine uptake. Stress raises blood glucose, exacerbating oxidative stress as in diabetes complications. Adrenals require nitric oxide to produce glucocorticoids, but chronic glucocorticoids increase oxidative stress and uncouple NOS—a vicious cycle. Mind-body connection is physiologically real.
Pathway 1: NOS/L-arginine. Pathway 2: Nitrate-nitrite-NO. Dietary/supplemental nitrate absorbs, concentrates in salivary glands, reduced to nitrite by tongue bacteria, swallowed into acidic stomach (some converts to NO, protecting against E. coli, H. pylori). Most nitrite absorbs; tissues reduce it to NO as needed (e.g., myoglobin in exercising muscle, cytochrome C oxidase in electron transport chain under oxidative stress for circulation/oxygen delivery). Avoids BH4/oxidative stress issues of NOS pathway, inhibits some free radicals/superoxide.
Nitric oxide downregulates inflammatory cytokines (IL-6, IL-8), NLRP3 (as in COVID/vaccine), vital for chronic issues with oxidative stress/inflammation causing nitric oxide deficiency. hsCRP reduces with nitrate support; example: doctor's hsCRP rose from 0.4 to 4.3 during virus, normalized with twice-daily supplement.
Insulin resistance, diabetes, metabolic syndrome are nitric oxide-deficient states. GLUT4 receptor requires nitric oxide to translocate and uptake glucose; deficiency raises blood glucose. Fasting glucose, insulin, A1C reduce with regular supplemental nitrate. High A1C binds nitric oxide tightly, reducing bioavailability for microcirculation and clotting prevention. Dysregulated glucose/insulin/metabolism lowers nitric oxide.
Nitric oxide deficiency leads to cardiovascular complications in diabetes and glucose dysregulation. Low nitric oxide impacts the electron transport chain, mitochondria, ATP production, and mitochondrial biogenesis. Mitochondrial biogenesis depends on nitric oxide for regeneration. The electron transport chain couples electrons to produce ATP and water, but some oxygen forms superoxide. Mitochondria are a major source of reactive oxygen species (ROS). Nitrite and nitric oxide recouple the electron transport chain, downregulating superoxide and ROS production.
Impaired endothelial NOS (eNOS) increases hypertension, myocardial infarction, heart attack, and stroke. Optimizing nitric oxide mitigates these via blood pressure normalization. High blood pressure precedes cognitive decline. Nitric oxide reduces plaque formation in vasculature and benefits POTS (postural orthostatic tachycardia syndrome) and dysautonomia.
Cardiovascular disease remains the world's number one killer, per recent studies. Optimizing nitric oxide governs circulation and microcirculation, recouping eNOS. Blood pressure normalization occurs with DASH diet or nitrate products. People with blood pressure issues often require multiple meds (even triple therapy), indicating underlying nitric oxide deficiency. Optimizing nitric oxide may avoid or reduce meds, alongside stress reduction, diet, and exercise.
Nitroglycerin (an organic nitrate) increases nitric oxide for heart attacks, metabolized differently from inorganic nitrates (vegetables/supplements). Organic nitrates like nitroglycerin and isosorbide cause resistance, requiring higher doses; inorganic nitrates do not.
Optimizing nitric oxide keeps blood vessels open, preventing plaque by reducing inflammatory damage. It benefits POTS patients via circulation modulation, including brain circulation.
Nitric oxide downregulates mast cell histamine release and inflammatory cytokines. Nitrate therapy lessens histamine issues.
Increasing nitric oxide improves brain microcirculation, cognitive function, brain fog, fatigue, anxiety, and depression. Brain (2% body weight) consumes 20% total oxygen; microcapillaries must open for oxygen delivery and debris removal. Brain circulation produces 25% of total body nitric oxide. Hemoglobin requires nitric oxide to release oxygen at microcapillary level, even if oxygen-saturated.
Poor circulation reduces nutrient delivery, oxygen, and waste removal, impairing detoxification.
Nitric oxide increases BDNF (brain-derived neurotrophic factor) for neuroplasticity. Neurons require constant feeding via microcapillaries as they cannot store ATP; long-lived neurons need ongoing nourishment and cleanup. Nitric oxide inhibits GABA transaminase, prolonging GABA circulation (calming neurotransmitter), reducing glutamate toxicity.
Nitric oxide is foundational; nitrate therapy alone reduced a friend's HSCRP (oxidative stress marker). Still pair with glutathione, melatonin, antioxidants for redox balance.
Nitric oxide supports kidney microcirculation, filtration, eGFR, and glomerular filtration rate (GFR). Dialysis removes 80% nitrate first pass, nearly all after hours, exacerbating kidney disease and cardiovascular risk. A kidney doctor uses nitrate products as base therapy.
Nitric oxide is essential for endogenous stem cell release, targeting, differentiation. Optimize before exogenous stem cells/exosomes; poor results often due to low nitric oxide. Hyperbaric therapy boosts stem cells via nitric oxide.
Erectile dysfunction (ED) signals endothelial dysfunction and early cardiovascular disease. PDE5 inhibitors (Viagra, Cialis) prolong existing nitric oxide; ineffective if deficient. Optimizing nitric oxide may eliminate need. Avoid with organic nitrates (different metabolism), but inorganic nitrates + PDE5 inhibitors allow lower doses with better results. Women need nitric oxide for sensation, response, lubrication.
NOS pathway: Arginine/citrulline supplements studied in young male athletes, not chronic illness, diabetes, or cardiovascular disease. Avoid arginine; citrulline slightly better but still forces dysfunctional uncoupled NOS. Few are truly arginine-deficient.
Beets support nitrate-nitrite-NO pathway; requires 7 oz (half pound).
Nitrate-nitrite-NO pathway is path of least resistance. Lozenges provide nitrite (20 min-1 hr half-life); nitrate (6-8 hr half-life) rebuilds microbiomes (mouth, gut, skin, vagina). Potassium nitrate is one ingredient.
Studies: 300-400 mg nitrate per dose for physiological changes (e.g., blood pressure). Beth's supplement: 320 mg nitrate per 2 capsules. Recommend 2 capsules morning + high-nitrate veggies (arugula salads) lunch/dinner. Use test strips to confirm vegetable sufficiency.
Antibacterial mouthwashes, fluoride/peroxide toothpastes disrupt oral microbiome, impairing nitrate-to-nitrite conversion, harming cardiovascular/systemic health. Nitrate toothpaste (e.g., for sensitive teeth) supports. Nitrate rebuilds microbiome even in severe cases (2 weeks for worst). Oral/gut microbiomes share 50% bacteria.
Nitrate works despite suboptimal oral microbiome; tests show saliva nitrate increase within 1 hour post-supplement.
Test strips: 1-1.5 hours post-nitrate for initial check. Muscles store nitrate/nitrite; daily replenishment needed (veggies/supplements). Over time, stores stabilize for more durable levels; test anytime shows steady if replete, but still replenish daily.
Methylene blue downregulates only upregulated iNOS, synergizes with nitric oxide: supports electron transport chain, creates mitochondrial hypoxia enabling cytochrome C oxidase to reduce nitrite to NO for vasodilation, cerebral blood flow, glucose uptake.
No observed excess nitric oxide cases; even septic shock uses nitrite for perfusion. Transcript cuts off here.
Methylene blue is used in treatments for septic shock, along with nitrite, to maintain perfusion. No cases of excessive nitric oxide have been observed. Excessive nitrate intake, such as 1200-1500 mg per day from the DASH diet, equates to two capsules four to five times a day, or 7 ounces of beets or 5 ounces of spinach four to five times a day, which is unrealistic. Peroxynitrite concerns are a non-issue.
So, no known contraindications then. And I'm assuming maybe in pregnancy not a great idea to do some of these things but what are your thoughts?
Only avoid in the last month of pregnancy. Every facet of fertility is nitric oxide mediated.
When nitric oxide seems like a fix-all due to its far-reaching implications, skepticism arises. Nitric oxide connects to every physiological process researched since 2009. It is not the only intervention but should form the base of every protocol by optimizing microcirculation. This enhances delivery of supplements, IVs, therapies like PEMF, allowing other treatments to work better.
Products include one targeted for women through Libby and another through Approved Medical Solutions.
Approved Medical Solutions product has third-party validation for no oxalates.
Ingredients and Rationale
Methylfolate and methyl B12 support the methylation cycle, BH4 production, and NOS enzyme coupling. Vitamin C acts as an antioxidant and reduces BH2 back to BH4, the only molecule that can do so. Contains potassium nitrate, hesperidin (supports cardiovascular health), and arugula (high nitrate, no oxalates, unlike beets or spinach).
which is great cuz that stuff tastes awful. So I'm happy to get it in a capsule.
Nitrate supplementation rebuilds microbiomes. Even in sick patients, salivary strips turned positive after weeks of continuous use.
Nitrate to Nitrite Conversion
Conversion occurs beyond the oral microbiome, in other body sites.
Dosing Recommendations
Serving size is two capsules, typically once a day, all at once, as a physiological dose. Add vegetables later in the day. For blood pressure management (to avoid or discontinue meds) or sexual dysfunction, use two capsules twice a day, or two capsules one hour prior to activity.
Links provided for Approved Medical Solutions product and Libby product (usable by men too).
Stress reduction activities, walking, eating plenty of vegetables and proteins with fewer carbs, turning off Wi-Fi at night. After computer work, walk around every hour. Supports nitric oxide twice a day, especially with current oxidative stress.
Don't forget to tell them that you support your nitric oxide.
Excellent. Excellent. This has been such a great conversation... so wonderful to hear all of the potential things that people can improve by looking into this nitric oxide arena.
Thank you very much. My pleasure.
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