Formulator’s Corner #10: A Nitrosigine-Powered Stimulant-Free Pre-Workout Supplement

At PricePlow, we love tracking trends, making sure we stay on top of the latest and greatest innovations and consumer demands in the dietary supplement industry. Two trends we’ve enjoyed watching are the growth in branded, clinically-verified ingredients, and the movement towards lower-stimulant and stimulant-free pre-workout supplements.

Nitrosigine

Move over L-arginine, Nitrosigine (inositol-stabilized arginine silicate) actually makes it work as originally desired!

As caffeine consumption has risen, more consumers are realizing that it’s a band-aid solution to energy. The trade-offs of higher caffeine consumption, which include reduced sleep quality, increased jitteriness, and its cardiovascular impact, have people looking for low-stim and zero-stim pre-workout alternatives — especially for evening workouts.

It’s been far too long since we’ve put together a Formulator’s Corner segment, where we dream up an ideal hypothetical formulation that any brand can take and run with, so Nutrition21 put us to the task. They asked for a unique stimulant-free pre-workout supplement to support blood flow and focus, but with their Nitrosigine® as the hero branded ingredient — without citrulline.

A hypothetical Nitrosigine-based stim-free pre-workout… without citrulline!

We came up with a formula that’s led by the patented inositol-stabilized arginine silicate ingredient (Nitrosigine) we’ve all come to know and love from Nutrition21, but with some added botanicals and conditionally-essential amino acids to keep athletes focused and training… without an insane price tag.

PricePlow Formulators Corner #10: Nutrition21's Nitrosigine Powered Stim-Free Pre-Workout Supplement

How would you craft a Nitrosigine-led stimulant-free pre-workout supplement with no citrulline and no other branded ingredients that’s unique and effective? Here’s how we would!

We also threw in a few bonus vitamins and mitochondrial-enhancers that we don’t see in too many pre-workouts, hoping to provide some zip without any reliance on caffeine.

The Nitrosigine advantage

Using Nitrosigine over citrulline provides several upsides:

  1. Nitrosigine provides more efficient dosing, so we can do more with less. A study we’ll cover below shows how 1.5 grams of Nitrosigine led to similar effects as 8 grams of citrulline malate
  2. Using lower doses here enable greater doses elsewhere, without having an expensive or enormous gut-busting scoop
  3. Removing citrulline reduces the burden of flavor systems, potentially requiring less malic acid and excipients, while opening up new flavor avenues.

The countless citrulline-based pre-workouts get wrapped into the same old flavor systems, scoop sizes, and form factors, so here, we’re showing a way to accomplish things differently.

Our hypothetical formula is below, but if you want to make it a reality, then contact us or Nutrition21 and get cracking! First, let’s have you sign up for PricePlow’s Nutrition21 and Nitrosigine alerts so that you don’t miss the next video or news article:

Subscribe to PricePlow's Newsletter and Alerts on These Topics

Topic Blog Posts YouTube Videos Instagram Posts
Inositol-Stabilized Arginine Silicate
Nitrosigine
Nutrition21

PricePlow’s Hypothetical Nitrosigine Stim-Free Performance Pre-Workout Supplement

First, let’s start with the hero — the nitric oxide promoting Nitrosigine and the rest of our nitric oxide blend:

  • Nitrosigine® (Inositol-Stabilized Arginine Silicate) – 1,500 mg

    PricePlow Formulators Corner #10: Nutrition21's Nitrosigine Powered Stim-Free Pre-Workout Supplement Ingredients

    This 21-gram scooper is anchored by Nitrosigine and bolstered by some botanicals and conditionally-essential amino acids, as well as a unique vitamin and mineral blend you don’t see here. There will be pumps… and a whole lot more!

    Nitrosigine® is a patented,[1] industry-leading nitric oxide-supporting ingredient designed and manufactured by Nutrition21. It’s sometimes referred to as inositol-stabilized arginine silicate, or ASI for short.

    Building a better arginine

    In the beginning of the dietary supplement industry, the amino acid L-arginine was the go-to nitric oxide (NO) supporting ingredient. This made intuitive sense, since arginine is the direct precursor to NO.

    However, as research matured, it became clear that arginine’s oral bioavailability is quite low – too low for it to be an effective supplement. The result, described by researchers as the arginine paradox,[2] was situation where arginine doses big enough to work were so big that they caused gastrointestinal problems.[3,4]

    This is because arginine has a higher affinity for the enzyme arginase, which degrades arginine, than it does for the enzyme endothelial nitric oxide synthase (eNOS), which is responsible for converting arginine into NO[5] (the latter is what we want in a workout situation). When arginine binds to arginase, it gets broken down before the body can turn it into NO, a phenomenon known as the first pass effect.[6-9]

    Thankfully, Nutrition21 developed and patented Nitrosigine, which doesn’t suffer such a fate.

    Nutrition21 Nitrosigine Graphic

    Nitrosigine is primarily found in pre-workouts due to its ability to boost nitric oxide levels… but don’t forget about its cognitive-supporting capabilities!

    Nitrosigine at 1,500 milligrams – long-lasting, fast-acting

    The standard clinical dose for Nitrosigine is 1,500 mg. Not only is this the best-studied dose of Nitrosigine, it’s actually the only one that’s been studied in randomized controlled trials. And what those trials have repeatedly found is that this dose of Nitrosigine can significantly upregulate NO after just one dose,[10,11] with the benefits compounding over time.[11]

    When it comes to onset and duration, this dose goes to work quickly: blood arginine levels begin increasing within 30 minutes of use, and remain elevated over 6 hours.[11,12]

    Helping formulators do more with less

    In one study, 1.5 grams of Nitrosigine went up against a whopping 8 grams of citrulline malate – and won. While both treatments increased blood flow to the same extent, Nitrosigine was 5x more effective, gram-for-gram. This study found that 1,500 mg Nitrosigine can increase flow-mediated dilation (FMD), a measure of arterial blood flow, by an impressive 31%.[10]

    Nutrition21 provided a graphic showing similar comparisons against other known ingredients — and we can guarantee you that it tastes a whole lot better than multiple grams of beet powder!

    Nitrosigine vs. Other Nitric Oxide Ingredients

    Nutrition21’s Nitrosigine against comparable ingredients — its flavor profile and lower dosage help formulators tremendously. Image courtesy Nutrition21

    Nitrosigine’s cognitive benefits

    We’ve all heard how increased NO production can benefit physical and athletic performance, by helping the cardiovascular system work more efficiently thanks to vasodilation. And to be sure, this is the primary reason for the inclusion of NO boosters like Nitrosigine in a pre-workout formula.

    Nitrosigine Upper Leg Pumps

    After 3 days of Nitrosigine use, upper leg pumps as measured by leg circumference were significantly increased![13]

    But as it turns out, upregulating NO can have some powerful benefits for cognition as well. After all, your brain needs the nutrients and oxygen from blood no less than the rest of your body – so it makes perfect sense that improving circulation systemically could help your brain work better, too.

    Nitrosigine studies have demonstrated that it can:

    We find that these benefits are especially beneficial in stimulant-free pre-workouts, as users seek added focus and perceived energy when they’re not relying on caffeine. This is why Nitrosigine works so well in so many products.

    Check out our comprehensive Nitrosigine discussion

    Nitrosigine 2022 Cognitive Study Infographic

    A nitric oxide booster that improves cognition?! Yes – Nutrition21 passed around this helpful infographic after the Nitrosigine cognition study on healthy young adults was published.[16]

    But wait, there’s more! If you want the full scoop on what Nitrosigine is and how it works, head on over to our previous blog post Nitrosigine: The Nitric Oxide Booster That Enhances Brain Function.

  • Pomegranate Extract (Punica granatum) – 1,000 mg

    So what unique botanicals can we add to Nitrosigine to provide some auxiliary effects that hit some different pathways, yet keep costs (and flavor) under control? Our first thought was an ingredient ignored in too many ergogenic supplements — pomegranate.

    In one 2014 study, scientists randomized 19 very fit, trained young men and women (average age, 22) to take either 1,000 mg of pomegranate extract (PE), or a placebo. After taking their treatment and undergoing a treadmill exercise test at an intensity level of 90% VO2max, their time to exhaustion was increased by an impressive 12%.

    At 100% VO2max – maximum intensity – the effect size was a little smaller, but still significant, with participants lasting 7% longer.[17]

    Nitric oxide (NO) synthesis

    According to the researchers behind that experiment, a big part of the PE’s endurance-boosting effect can be explained by its ability to upregulate nitric oxide (NO).[17] Pomegranate also has a documented ability to stabilize the NO molecule, protecting it from oxidative degradation.[18] Since NO is a particularly unstable molecule by nature, this mechanism leads to a pretty big increase in overall NO activity. Other studies have shown additional protective effects from pomegranate’s NO gains.[19]

    Mitochondrial health: The power of urolithin A inside

    Thanks to a particular bioactive constituent, urolithin A, pomegranate extract supplementation has been shown to significantly improve mitochondrial function in preclinical research.[20] Further research on middle-aged humans with urolithin A itself has even shown improvements aerobic endurance improvements as measured by peak oxygen consumption, with biomarkers indicating higher mitochondrial efficiency and reduced inflammation.[21] It’s also been shown to be safe.

    Exercise recovery

    Pomegranate also has anti-inflammatory effects,[22,23] and has been shown to help facilitate recovery from exercise, particularly weightlifting.[24]

    In one study where nine elite weightlifters drank PJ before an Olympic lifting session, their post-workout muscle soreness and blood pressure were significantly lower compared to placebo.[24] Their total volume performance also went up significantly, by about 8%.

    Pomegranate Juice Performance Graph

    Pomegranate juice intake in trained weightlifters caused a substantial boost in performance. Note the significant differences between PLA and POMj conditions.[24]

    Testosterone booster

    But there’s one area in particular where pomegranate has gotten lots of attention lately, and that is testosterone boosting. In a 2015 study, men and women consumed 0.5 liters (roughly 16 ounces) of pomegranate juice daily. By the time two weeks had passed, the men’s testosterone levels had risen by an impressive 24%.[25] That’s a huge effect size – we rarely, if ever, see effect sizes that big in general, but especially not in testosterone-boosting studies.

    The same study found that the PJ significantly decreased the subjects’ cortisol levels. Morning cortisol fell by roughly 50%, while midday cortisol was reduced by roughly 25%.[25] Not only is reducing cortisol great for health in itself, but it’s also good since cortisol is a testosterone antagonist.

    This helped back up a 2008 animal study that found almost exactly the same thing – a boost in T levels to the tune of 24%.[26]

    Pomegranate is hypothesized to have these androgenic effects largely because it reduces oxidative stress in testicular tissue.[25,26] In fact, the rat study actually found that its juice significantly increased the testicular weight of the rats who drank it.[26]

  • Amla Fruit Extract (Phyllanthus emblica) – 250 mg

    Amla actually has not one, but two scientific names – Phyllanthus emblica and Emblica officinalis. It’s a fruit tree long used to treat circulatory conditions and improve overall cardiovascular function.[27]

    Antioxidant compounds in amla have been identified as capable of improving endothelial function while simultaneously discouraging the formation of platelets,[28] supporting heart health.

    Amla’s ability to upregulate nitric oxide (NO)

    Nitrosigine Working Memory Study

    A study published in late 2021 showed that Nutrition21’s Nitrosigine improves working memory and cognitive function in healthy young adults[16]

    One of the bioactive constituents responsible for this effect is gallic acid, a phenol antioxidant that occurs naturally in amla fruit[29] and can help stabilize eNOS, protecting it from oxidative stress. Ultimately, this increases eNOS activity, and NO synthesis.[30]

    While gallic acid is important, amla extracts are generally standardized for a class of bioactive constituents called low molecular weight tannins (LMWTs). Molecules in the LMWT class include emblicanin-A, emblicanin-B, punigluconin, and pedunculagin.[31] The human body metabolizes these into urolithins A, B, C, and D,[32] which are all known to significantly improve mitochondrial function.[33]

    In addition to increasing ATP production, urolithin B may also have anabolic effects.[34] Amla extract supplementation is even associated with cognitive benefits.[35] This brings us to the next section:

    Now for the endurance and focus blend:

  • Beta Alanine – 6,400 mg

    As an ergogenic aid, beta-alanine can help optimize athletic performance by augmenting your body’s capacity for physical exercise.

    Beta Alanine Benefits

    We’re interested in section (B) here, where beta alanine alone shows great results compared to placebo.[36]

    When beta-alanine is combined with the amino acid histidine, the result is carnosine, a dipeptide molecule that your body uses to eliminate lactic acid from muscle tissue. This helps endurance because lactic acid buildup causes muscular fatigue, so accelerating the removal of lactic acid can help prevent fatigue, resulting in a pro-endurance effect.[37]

    There’s generally no need to supplement with histidine, since it naturally occurs at high concentrations in commonly eaten foods. Thus, beta alanine is almost always your body’s bottleneck on carnosine synthesis, making beta alanine supplementation the most intelligent strategy for increasing carnosine.[38,39]

    Peer-reviewed literature on beta alanine suggests that it’s most effective at increasing endurance during exercises conducted at a specific intensity level – namely, anything that can be sustained for 30 seconds to 10 minutes.[36,40]

    Big dose alert: why 6.4 grams over 3.2?

    As opposed to the standard We went big with a 6.4 gram dose of beta-alanine to help get users to carnosine saturation faster. There are a few studies showing how well 6.4 grams works in this fashion,[39,41-43] so consider it if you’re cool with the beta alanine tingles, discussed next:

    Tingles are coming, but they’re non-toxic

    If, after taking beta alanine, you experience a tingling sensation in your face and upper body, don’t worry about it – a recent safety review concluded that this common beta alanine side effect is perfectly normal and harmless.[44]

  • Taurine – 2,000 mg

    When it comes to pre-workout formulas, the amino acid taurine shines as an osmolyte.[45] Osmolytes get their name from the fact that they can increase the water content of cells by affecting the osmotic pressure gradient across cellular membranes.

    Taurine Endurance

    Taurine’s effect on endurance, with success in doses anywhere from 1 gram to 6 grams.[46]

    Once laden with water, these hyperhydrated cells have better access to nutrients, can get rid of metabolic waste more efficiently, and are less adversely affected by heat stress. As a result, they can work harder, for longer, which shows up as increased aerobic and anaerobic endurance.[46]

    Research shows that taurine, like Nitrosigine, takes effect upon first use. According to a 2018 meta-analysis, just one 1,000 mg dose of taurine – only half of what’s proposed here – can significantly improve athletic endurance.[46]

    It’s also a powerful antioxidant[47,48] that can help support the body during exercise-related stress, on top of supporting calcium signaling in muscle cells.[49]

    Brain benefits

    Taurine has interesting effects in the central nervous system (CNS), where it functions as a GABAergic compound, meaning it mimics the effects of the neurotransmitter GABA, providing a calming anti-inflammatory effect on brain and nerve cells.[50] It can even trigger the production of new mitochondria in the brain.[50]

    Yet taurine is also dopaminergic,[51] meaning it upregulates dopamine, the neurotransmitter most closely associated with focus and motivation. This makes taurine an absolute no-brainer for this formula, since feeling good emotionally and mentally is paramount for having a good workout.

    Taurine Browning of Fat

    Taurine can induce the browning of fat,[52] which is important because brown fat is more mitochondrial-dense and metabolically active!

    Promotes white adipose tissue (WAT) over brown adipose tissue (BAT)

    Finally, taurine can have significant anti-obesity effects. It does this by stimulating the creation of new mitochondria in fat cells, which can convert white adipose tissue (WAT) into metabolically-active brown adipose tissue (BAT).[53] Taurine can also selectively inhibit the growth of new WAT cells, while allowing BAT cells to proliferate.[54] More BAT can lead to greater daily caloric expenditure.[52]

    Beyond that, taurine has been shown to lower inflammation and high blood glucose levels often associated with being overfat.[55]

    Awesome dose!

    One thing we wanted in this formula is a 2,000 mg dose. Since the latest research suggests that taurine’s effects are dose-dependent,[56] with intake levels of up to 10 grams per day being safe for human consumption,[56] this is one of those times where we can safely have a “more is better” mentality (within reason) when it comes to taurine. Its conditionally essential status makes it important for people with elevated metabolic requirements, like athletes.[46,50,57]

  • L-Tyrosine – 2,000 mg

    Tyrosine is an amino acid and important precursor to catecholamine neurotransmitters like dopamine and adrenaline. By increasing the production of these neurotransmitters through tyrosine supplementation, it’s possible to improve your mood, sharpen your focus, and even optimize athletic performance while making your body more resilient in the face of stress.[58]

    All Black Everything ABE Pump

    All Black Everything’s ABE Pump has a unique combination of both Nitrosigine and creatine monohydrate to keep the pumps coming strong

    Tyrosine has such a significant effect on brain chemistry that it can actually increase working memory[59] and cognitive flexibility,[60] a measure of multitasking ability. It’s also great at supporting cognitive function during sleep deprivation.[61]

    How tyrosine helps the thyroid

    Additionally, tyrosine supports the thyroid gland, whose function is a factor in exercise performance[62] and recovery.[63] Tyrosine helps with this because it’s a thyroid hormone precursor – it can help support your body’s production of triiodothyronine and thyroxine,[64] your body’s two thyroid hormones.

    Research in animals has shown that tyrosine deficiency can cause thyroid hormone deficiency.[65] Strenuous exercise or caloric restriction can also downregulate thyroid hormone production,[66,67] and that can subsequently lead to a drop in basal metabolic rate.[68] So if you’re restricting calories to lose fat, tyrosine can potentially help mitigate the drop in thyroid hormone associated with this.[66]

    Just 100 milligrams is enough to significantly increase blood tyrosine levels.[69-72] We have 20 times that dose here, so rest assured that it’s an efficacious one.

  • L-Ornithine Alpha-Ketoglutarate – 2,000 mg

    L-ornithine alpha-ketoglutarate (OKG) is a chemical complex of the amino acid ornithine and a keto acid called alpha-ketoglutarate.

    Soul Performance Nutrition Aura Endorphin Flow Pre-Workout

    Soul Performance Nutrition Aura Endorphin Flow is a pre-workout that flows, thanks to plenty of electrolytes/osmolytes and nitric oxide boosting Nitrosigine that also supports cognition!

    The ornithine in this molecule can help your body eliminate ammonia, a metabolic waste product that accumulates during exercise. Since ammonia can create muscular fatigue and compromise physical performance,[73] getting rid of it faster via ornithine supplementation can have an endurance-boosting effect.[73,74]

    On the other hand, alpha-ketoglutarate plays a key role in the Krebs cycle, the metabolic process that your body uses to generate cellular energy.

    Ornithine also also been identified as a growth hormone (GH) secretagogue, meaning it upregulates GH.[75,76] As most readers probably know, GH is considered an anabolic compound, which plays a role not only in the growth of muscles, but in many other kinds of cells and tissues as well. Exogenous GH has been used successfully for adding muscle, shedding fat, and optimizing both recovery and performance.

    When it comes to optimizing hormones, recovering from exercise, and optimizing muscle protein synthesis, there’s arguably nothing more important than getting good sleep, and fortunately, it appears that ornithine can help us with that as well. According to one study, taking ornithine can significantly increase your body’s ratio of DHEA to cortisol,[77] which is an important stress biomarker and tightly correlated with sleep quality.

    Why take ornithine with AKG

    OK, so ornithine is cool – what’s the point of using the AKG-bound molecule?

    For one thing, since AKG is a natural metabolite of ornithine, taking it together with ornithine can help discourage the body from converting ingested ornithine into AKG. This naturally encourages the formation of other metabolites, like arginine.[78,79]

    What’s more, AKG has ammonia buffering effects of its own, and can help the body get rid of ammonia.[80]

  • Pyrroloquinoline Quinone Disodium Salt (PQQ) – 20 mg

    Pyrroloquinoline quinone (PQQ) is a special salt that can stimulate mitochondrial biogenesis,[81,82] the mechanism by which your body generates new mitochondria. It does this by activating a cluster of signaling proteins called sirtuin 1 (SIRT1).[81]

    Nitrosigine vs. Citrulline Malate (Mean Corrected FMD Change)

    Nitrosigine vs. Citrulline Malate (Mean Corrected FMD Change).[10] Image courtesy Nutrition21

    Again, higher mitochondrial density means more ATP produced, and hence, increased circulation and oxygen uptake.[83] This is a huge boost, not only for performance and recovery, but also for overall health and, as science is increasingly finding, longevity.

    In the brain, PQQ’s effects manifest as better cognitive performance,[84] which is why PQQ is often used in nootropic applications to reduce stress, increase energy, and even enhance sleep quality.[85]

    Note that this dose of PQQ, as pyrroloquinoline quinone disodium salt, adds about 2.5 milligrams of sodium — negligible but worth mentioning for those who really care around here. We add a whole lot more sodium below.

    Now how about a vitamin blend that’s not the same old B6/B12 mixture we always see:

  • Potassium – 470 mg (10% DV)

    Potassium is an electrolyte mineral, and unfortunately, a major shortfall nutrient in the Standard American Diet (aptly abbreviated as SAD).[86]

    Historically, human beings consumed lots of potassium, but with the rise of processed food, which generally has the potassium stripped out of it, plus declining average intakes of fresh produce, there’s been a huge drop in the overall potassium intake.[86-88]

    Potassium also has to exist in a balance with its antagonist, sodium – and put simply, Americans consume way too much sodium, and not nearly enough potassium.[89] Unless you’re eating tons of fruits and vegetables like potatoes, carrots, beans, tomatoes, prunes, and bananas, you’re probably low in potassium too.[90]

    PricePlow Formulators Corner #10: Nutrition21's Nitrosigine Powered Stim-Free Pre-Workout Supplement

    Three sources of potassium inside!

    Whenever PricePlow writes about potassium, we love to bring up a study titled “Food pattern modeling shows that the 2010 Dietary Guidelines for sodium and potassium cannot be met simultaneously”, which more or less proves that when following official US government dietary guidelines, it’s impossible in practice to keep potassium above the minimum recommended level, while simultaneously keeping sodium below the recommended maximum level.[91]

    The benefits of potassium

    Potassium is touted primarily for its cardiovascular effects – while sodium is generally understood to raise blood pressure, potassium lowers it.[86]

    However, it’s important to stress that since sodium and potassium exist in an antagonistic relationship to each other, the ratio of sodium intake to potassium intake matters just as much, if not more, than the absolute intake of each nutrient. The research literature demonstrates pretty conclusively that the interaction between sodium and potassium is heavily implicated in the onset of hypertension,[92] with several studies showing that hypertension and cardiovascular disease are linked to lower potassium-to-sodium ratios.[93-97]

    And of course, there are two strategies for fixing this ratio – cutting sodium is one, but increasing potassium is another.

    Higher potassium-to-sodium intake ratios are associated with lower blood pressure and reduced heart disease risk, and increasing the ratio by increasing potassium intake generally has a bigger effect than simply restricting sodium.[90,98] This is especially true if you’re an athlete, or anyone who sweats a lot, because we lose lots of sodium in sweat, and failing to replace that lost sodium comes with health issues of its own.

    And again, sodium restriction is difficult to achieve in practice,[89,91] so adding potassium is the safer bet.

    While there aren’t many studies looking specifically at the connection between potassium and performance, the theoretical basis for such a connection definitely exists thanks to potassium’s ability to improve cardiovascular health and bone mineral density.[99,100]

    Note: Potassium comes from three sources in our formula – potassium citrate, potassium gluconate, and Nitrosigine itself!

  • Sodium (from Sodium Chloride) – 230 mg (10% DV)

    Next up, we have sodium — here, we’re specifically focusing on what comes from the sodium chloride (table salt), although a tiny portion of sodium (~2.5mg) also comes from the PQQ ingredient.

    While sodium has gotten a bad rap, we want to remind you, per our discussion in the preceding section on potassium, that the ratio is what really matters here. And since we have a great potassium to sodium ratio in this pre-workout formula, there’s little reason to worry about the sodium used here.

    Soul Performance Nutrition Sodium

    Image courtesy Soul Performance Nutrition

    For one thing, let’s put 230 mg of sodium in context – if you add up all the other sodium you’re getting from food and supplements, you’ll probably find that this accounts for 10% or less of all the sodium you eat in a day.

    Either way, in our opinion, a significant dose of sodium is a good thing for a pre-workout formula regardless of how much potassium there is. That’s because we lose a lot of sodium in sweat, and after all, you should be sweating a lot during your workouts! That means front-loading a little sodium, to pre-emptively offset what you’ll lose during exercise, is probably not a bad idea.

    In fact, if you sweat too much without replacing lost sodium, then you can actually end up sodium depleted, which is not great since your body needs sodium for muscular contraction.[101] Muscles that lack sodium usually can’t function at their full capacity.[102]

    Emerging epidemiological research on sodium

    In one of history’s great ironies, emerging research suggests that the consequences of eating too little sodium may actually be the same as ingesting too much. A meta-analysis of the research literature on sodium found a J-shaped association between sodium intake and the risk of cardiovascular events, based on studies that included over 300,000 cumulative participants. The data in this meta-analysis showed that the lowest risk of cardiovascular events and death is associated with a sodium intake between 3 and 5 grams per day.[103]

    Alpha Lions Gain Candy Nitrosigine

    Clinically-studied Nitrosigine in single-ingredient pill form: Alpha Lion Gains Candy Nitrosigine

    That is, the study didn’t find any increase in cardiovascular mortality until daily intakes exceed 5 grams per day, which is way above the current maximum of 2,300 mg. And by the same token, cardiovascular mortality was associated with intakes less than 3,000 mg/day – which is still above the 2,300 mg maximum![103]

    Another study, published in 2011 by the Journal of American Medicine, which was carried out with over 28,000 subjects, concluded that urinary sodium excretion below 3,000 mg/day – urinary sodium excretion being a proxy measure for sodium intake – actually increased one’s risk of hospitalization for congestive heart failure![104]

    The same 2011 study found that intakes of up to 7,000 mg/day do not, on average, raise a person’s risk of cardiovascular disease.[105]

    Sodium disclaimer

    None of this is medical advice – human biology is highly individual, and everybody will respond differently. If you’re not sure about how much sodium you should eat, ask your doctor.

  • Vitamin B1 (as Thiamine HCl) – 1.2 mg (100% DV)

    Thiamine (or thiamin) is one of the most important cofactors your body needs for adenosine triphosphate (ATP) production.[106] ATP is very important for health and performance, since it’s your body’s energy currency, the form of energy that’s actually used by your cells to perform metabolic tasks and nearly every task in the body.

    In the case of thiamine deficiency, ATP synthesis can be compromised, which results in significant neuronal loss due to lack of cellular energy.[107] This is a syndrome known as Wernicke-Korsakoff encephalopathy, and is commonly associated with late-stage alcoholism since chronic alcohol intake consumes thiamine.

    Thiamine is also involved in glucose metabolism,[108] and type 2 diabetics commonly have low thiamine levels. In some studies, taking extra thiamine has even been shown to reduce high blood glucose in people with metabolic concerns.[109,110] Overall, this suggests that thiamine may play a role in supporting healthy carbohydrate/glucose metabolism.

  • Folate (as Calcium L-5-Methyltetrahydrofolate) – 400 mcg DFE (100% DV)

    Calcium L-5-methyltetrahydrofolic acid (L-5-Methyl-THF-Calcium) is a special form of 5-methyltetrahydrofolate (5-MTHF), a methylated folate (vitamin B9) molecule. When you stack it up against other kinds of folate, 5-MTHF shows much better bioavailability than its competitors.[111-113]

    Folate deficiency has been shown to significantly increase the risk of developing several health issues.[114-117]

    In this context, homocysteine regulation is of concern because high homocysteine caused by low folate can cause major damage to your cardiovascular system, similar to vitamin B6 deficiency.[118]

    In this complicated metabolic pathway, your body controls homocysteine through the conversion of dietary folate (usually in the form of folic acid). One key part of this process is an enzyme called methylenetetrahydrofolate reductase (MTHFR) whose function is compromised in the large minority of the population with certain genetic mutations.[119]

    Your body can actually synthesize its own 5-MTHF from folic acid with an enzyme called methylenetetrahydrofolate reductase (MTHFR). A large minority of the population – up to 40% of people, according to one study[120] – possess one or more genetic polymorphisms that can interfere with the function of MTHFR, which ultimately raises the carrier’s risk of folate deficiency and increased blood homocysteine.

    The easiest and most reliable way around this potential bottleneck is supplementing directly with 5-MTHF, as we are doing here, as opposed to taking folic acid.

    Studies show that 5-MTHF supplementation can:

    • Increase serum plasma folate levels[111,113]
    • Reduce blood homocysteine levels by roughly 15%[121]
    • Increase the folate content of erythrocytes (red blood cells) by about 23%[121]
    • Support mood and cognitive status[122,123]
  • Vitamin B12 (as Methylcobalamin) – 2.4 mcg (100% DV)

    Methylcobalamin is our preferred form of B12 because, again, it’s methylated. Just like the rest of the methylated B vitamins, methylcobalamin can act as a methyl donor, meaning it can transport methyl groups to the site of methylation-dependent cellular-metabolic processes.[124]

    Vitamin B12 is crucial for red blood cell production, and severe B12 deficiency can result in a condition called megaloblastic anemia,[125,126] where red blood cells increase in size while becoming less numerous, which causes a net decrease in aerobic capacity.

    Just like folate, vitamin B12’s pro-methylation power means that it can help keep blood homocysteine levels under control. Some research has found that low B12 is linked to a significantly increased risk of birth defects, because of the homocysteine connection.[127-129]

    Vitamin B12 Deficiency and Homocysteine

    Similar to folate, B12 plays a key role in helping keep your serum homocysteine level under control. Because of this – and its role as a precursor to S-adenosylmethionine (SAMe) – even slight B12 deficiencies can lead to irreversible cerebral atrophy.[130]

    CAPTION: Similar to folate, B12 plays a key role in helping keep your serum homocysteine level under control. Because of this – and its role as a precursor to S-adenosylmethionine (SAMe) – even slight B12 deficiencies can lead to irreversible cerebral atrophy.[130]

    Even mild B12 deficiencies – the low side of the normal range, even – have been linked to reduced memory performance,[131] thanks partly to B12’s impact on serum homocysteine.[130] But B12 is also an important precursor to S-adenosylmethionine (SAMe), which is important for methylation, myelination, and phospholipid production in the central nervous system.[130]

    Evidence of B12’s ability to improve energy in people without a deficiency remains inconclusive, but fatigue is an early sign of depleted B12,[132] and something we can easily prevent with a moderate dose of methylcobalamin.

    Although it isn’t clear that B12 supplementation can increase energy levels in people who aren’t B12 deficient, fatigue is an early sign of B12 deficiency,[55] and something we obviously would like to avoid.

  • Iodine (as potassium iodide) – 196 mcg (130% DV)

    When it comes to promoting overall health and body composition, there’s perhaps nothing more important than optimal thyroid function. And unfortunately, if you have hypothyroidism, your odds of not getting a diagnosis are roughly the same as your odds of getting diagnosed.[133]

    And if hypothyroidism is an issue, then iodine deficiency is a potential culprit. Iodine is absolutely crucial for proper thyroid function – and unfortunately, more and more of us are ending up iodine deficient.[134]

    Iodine displacement – competition from halogens

    Functional iodine deficiency can have multiple causes, though. The first, and most obvious, is that your dietary intake of iodine is simply inadequate.

    Thyroid Metabolism Regulation

    The thyroid affects nearly everything,[68] and we want it functioning as well possible. Appropriate iodine and active vitamin A are two critically important components for that.

    Bromine is now a food additive in bread,[135] as opposed to how bread was once fortified with iodine in America.[136] As we all know, table salt is commonly still iodized, but with a burgeoning shift in consumer preference toward sea salt and pink Himalayan salt, which do not contain significant amounts of iodine, this has become a less reliable source of iodine in the American diet.

    So as iodine has been zeroed out of our food, we obviously consume increasingly less of it on average.

    But unfortunately, there’s an even bigger issue when it comes to dietary iodine – a general public issue is growing over the appearance of low iodine status, even in industrialized countries. The causes of this are under debate, with some arguing that iodine competitors such as bromine, chlorine, and fluoride displacement are to blame,[137,138] while others state this has just been a shift in consumer preferences.

    Regardless, the more of these competing halogens you consume – and it’s easy to consume lots of them, – the more they will force iodine out of your thyroid, thus leading to a drop in overall thyroid function.[139,140]

    For these reasons, iodine deficiency, a public health problem that was thought to have been permanently vanquished in the early 20th century, is now making a resurgence in the United States.[134]

    How iodine works in the thyroid

    Your body’s two main thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are directly regulated by your body’s access to iodine.[141]

    The amount of T3 you produce, in particular, plays an enormous part in determining the health of your heart, brain, and digestive tract.[142] Your basal metabolic rate, the rate at which your body burns calories at rest, is also established by T3.[142]

    Thyroxine

    Long story short: No iodine or tyrosine, no thyroid hormone synthesis. Get enough iodine and tyrosine in!!

    If you don’t have enough T3, then you’re at serious risk of developing hypothyroidism. If that should occur, then you can be sure that your metabolism with slow down, and you’ll probably gain significant amounts of fat.[143] Hypothyroidism also increases the likelihood of developing further issues, too.[144,145]

    Hypothyroidism can also cause:

    • Chronic fatigue[146]
    • Weakness[146]
    • Decreased cold tolerance[68]
    • Decreased amounts of brown adipose tissue (BAT)[147]
    • Decreased heart rate[148]
    • Smaller and less functional hippocampus, the region of the brain that handles learning and memory[149]

    All things we wish to combat — and if we’re going to include tyrosine here, we might as well also include some iodine.

Subscribe to PricePlow on YouTube!

Conclusion: Nitrosigine in the front, unique botanicals, vitamins, and minerals in the back

Nutrition21 Ghost V3 Nitrosigine

Ghost Legend V3 is out, and they kept one of the biggest changes from V2: a full 1.5g dose of Nitrosigine. In this article, we explore why. With all of the research and formulation talk out there, the answer is ultimately very simple.

We tire of seeing the same old, same old pre-workout supplements with citrulline, caffeine, and beta alanine. With no citrulline, we can open up to new flavor options, and move a ton of the product’s weight into other ingredients that offer more diverse benefits.

So what we did is take the tried-and-true, trusted nitric oxide ingredient in Nitrosigine and add in some of our favorite botanicals to make a more unique pump blend. After that, we added some key conditionally essential ingredients like taurine, tyrosine, and ornithine, which we like seeing together.

But we didn’t leave vitamins and minerals hanging – we doubled down on some of the higher-quality forms, bringing plenty of minerals to support a workout. And just in case, one of those minerals is iodine, which we fear too many people are getting too little of in the sea of halogen competition in our environment.

This is a hypothetical formula that’s free for anyone to use – but if you use it, make sure you let us know so we can put it on blast and give Nitrosigine the credit it deserves as the hero pump ingredient!

Subscribe to PricePlow's Newsletter and Alerts on These Topics

Topic Blog Posts YouTube Videos Instagram Posts
Inositol-Stabilized Arginine Silicate
Nitrosigine
Nutrition21

About the Author: Mike Roberto

Mike Roberto

Mike Roberto is a research scientist and water sports athlete who founded PricePlow. He is an n=1 diet experimenter with extensive experience in supplementation and dietary modification, whose personal expertise stems from several experiments done on himself while sharing lab tests.

Mike's goal is to bridge the gap between nutritional research scientists and non-academics who seek to better their health in a system that has catastrophically failed the public. Mike is currently experimenting with a low Vitamin A diet.

No Comments | Posted in , | Tagged , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

References

  1. Vijaya Juturu V., Komorowski, JR. 2002. US7576132B2 – “Arginine Silicate Inositol Complex and use Thereof.” The United States Patent and Trademark Office. https://patents.google.com/patent/US7576132
  2. Elms, Shawn, et al. “Insights into the Arginine Paradox: Evidence against the Importance of Subcellular Location of Arginase and ENOS.” American Journal of Physiology – Heart and Circulatory Physiology, vol. 305, no. 5, 1 Sept. 2013, p. H651, 10.1152/ajpheart.00755.2012; https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC3761326/
  3. Grimble, George K. “Adverse Gastrointestinal Effects of Arginine and Related Amino Acids.” The Journal of Nutrition, vol. 137, no. 6, 1 June 2007, pp. 1693S1701S, 10.1093/jn/137.6.1693s; https://pubmed.ncbi.nlm.nih.gov/17513449/
  4. Kaore, Shilpa N., et al. “Citrulline: Pharmacological Perspectives and Its Role as an Emerging Biomarker in Future.” Fundamental & Clinical Pharmacology, vol. 27, no. 1, 31 July 2012, pp. 35–50, 10.1111/j.1472-8206.2012.01059.x; https://pubmed.ncbi.nlm.nih.gov/23316808/
  5. Stamler, Jonathan S., and Gerhard Meissner. “Physiology of Nitric Oxide in Skeletal Muscle.” Physiological Reviews, vol. 81, no. 1, 1 Jan. 2001, pp. 209–237, 10.1152/physrev.2001.81.1.209; https://journals.physiology.org/doi/full/10.1152/physrev.2001.81.1.209
  6. Castillo, L, et al. “Splanchnic Metabolism of Dietary Arginine in Relation to Nitric Oxide Synthesis in Normal Adult Man.” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 1, 1 Jan. 1993, pp. 193–197; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC45626/
  7. Wu, Guoyao. “Intestinal Mucosal Amino Acid Catabolism.” The Journal of Nutrition, vol. 128, no. 8, 1 Aug. 1998, pp. 1249–1252, 10.1093/jn/128.8.1249; https://academic.oup.com/jn/article/128/8/1249/4722724
  8. O’sullivan, D., et al. “Hepatic Zonation of the Catabolism of Arginine and Ornithine in the Perfused Rat Liver.” Biochemical Journal, vol. 330, no. Pt 2, 1 Mar. 1998, p. 627, 10.1042/bj3300627; https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC1219183/
  9. van de Poll, Marcel CG, et al. “Interorgan Amino Acid Exchange in Humans: Consequences for Arginine and Citrulline Metabolism.” The American Journal of Clinical Nutrition, vol. 85, no. 1, 1 Jan. 2007, pp. 167–172, 10.1093/ajcn/85.1.167; https://pubmed.ncbi.nlm.nih.gov/17209193/
  10. Rogers, Jeffrey M et al. “Acute effects of Nitrosigine and citrulline malate on vasodilation in young adults.” Journal of the International Society of Sports Nutrition vol. 17,1 12. 24 Feb. 2020, doi:10.1186/s12970-020-00343-y; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041093/
  11. Kalman, Douglas, et al. “A Clinical Evaluation to Determine the Safety, Pharmacokinetics, and Pharmacodynamics of an Inositol-Stabilized Arginine Silicate Dietary Supplement in Healthy Adult Males.” Clinical Pharmacology: Advances and Applications, Oct. 2015, p. 103, doi:10.2147/cpaa.s84206; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603712/
  12. Komorowski, J., et al. Apr. 2016. “A Pharmacokinetic Evaluation of the Duration of Effect of Inositol- Stabilized Arginine Silicate and Arginine Hydrochloride in Healthy Adult Males.” The Journal of the Federation of American Societies for Experimental Biology vol. 30. https://www.fasebj.org/doi/abs/10.1096/fasebj.30.1_supplement.690.17
  13. Greenberg, Danielle, et al. “Inositol-Stabilized Arginine Silicate Reduces Exercise Induced Muscle Damage and Increases Perceived Energy.” Journal of Exercise and Nutrition, vol. 6, no. 1, 1 Mar. 2023, doi:10.53520/jen2023.103141; https://www.journalofexerciseandnutrition.com/index.php/JEN/article/view/141
  14. Evans, M. et al. July 2020. “Inositol-Stabilized Arginine Silicate Improves Post Exercise Cognitive Function in Recreationally Active, Healthy Males: A Randomized, Double-Blind, Placebo-Controlled Crossover Study.” Journal of Exercise and Nutrition vol. 3,3; https://www.journalofexerciseandnutrition.com/index.php/JEN/article/view/69 (full-text PDF, 2018 ISSN Poster Presentation, 2018 ISSN Conference Summary)
  15. Kalman, Douglas et al. “Randomized Prospective Double-Blind Studies to Evaluate the Cognitive Effects of Inositol-Stabilized Arginine Silicate in Healthy Physically Active Adults.” Nutrients vol. 8,11 736. 18 Nov. 2016, doi:10.3390/nu8110736; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133120/ (2018 ISSN Summary, 2018 ISSN Poster Presentation)
  16. Gills, Joshua L., et al. “Acute Inositol-Stabilized Arginine Silicate Improves Cognitive Outcomes in Healthy Adults.” Nutrients, vol. 13, no. 12, 1 Dec. 2021, 10.3390/nu13124272; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8703995/
  17. ‌Trexler, Eric T et al. “Effects of pomegranate extract on blood flow and running time to exhaustion.” Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme vol. 39,9 (2014): 1038-42. doi:10.1139/apnm-2014-0137 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4146683/
  18. Hord, Norman G et al. “Food sources of nitrates and nitrites: the physiologic context for potential health benefits.” The American journal of clinical nutrition vol. 90,1 (2009): 1-10. doi:10.3945/ajcn.2008.27131 https://academic.oup.com/ajcn/article/90/1/1/4596750?login=false
  19. de Nigris, Filomena et al. “Beneficial effects of pomegranate juice on oxidation-sensitive genes and endothelial nitric oxide synthase activity at sites of perturbed shear stress.” Proceedings of the National Academy of Sciences of the United States of America vol. 102,13 (2005): 4896-901. doi:10.1073/pnas.0500998102 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC555721/
  20. Sun, Wenyan et al. “Pomegranate extract decreases oxidative stress and alleviates mitochondrial impairment by activating AMPK-Nrf2 in hypothalamic paraventricular nucleus of spontaneously hypertensive rats.” Scientific reports vol. 6 34246. 7 Oct. 2016, doi:10.1038/srep34246. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5054377/
  21. Singh, Anurag, et al. “Urolithin a Improves Muscle Strength, Exercise Performance, and Biomarkers of Mitochondrial Health in a Randomized Trial in Middle-Aged Adults.” Cell Reports Medicine, vol. 3, no. 5, May 2022, p. 100633, doi:10.1016/j.xcrm.2022.100633. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9133463/
  22. Sohrab, Golbon et al. “Effects of pomegranate juice consumption on inflammatory markers in patients with type 2 diabetes: A randomized, placebo-controlled trial.” Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences vol. 19,3 (2014): 215-20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4061642/
  23. Danesi, Francesca, and Lynnette R Ferguson. “Could Pomegranate Juice Help in the Control of Inflammatory Diseases?.” Nutrients vol. 9,9 958. 30 Aug. 2017, doi:10.3390/nu9090958 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622718/
  24. Ammar, Achraf et al. “Pomegranate Supplementation Accelerates Recovery of Muscle Damage and Soreness and Inflammatory Markers after a Weightlifting Training Session.” PloS one vol. 11,10 e0160305. 20 Oct. 2016, doi:10.1371/journal.pone.0160305 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5072630/
  25. Al-Dujaili, Emad, and Nacer Smail. “Pomegranate Juice Intake Enhances Salivary Testosterone Levels and Improves Mood and Well Being in Healthy Men and Women.” Www.endocrine-Abstracts.org, BioScientifica, 1 Mar. 2012, www.endocrine-abstracts.org/ea/0028/ea0028P313
  26. Türk, Gaffari et al. “Effects of pomegranate juice consumption on sperm quality, spermatogenic cell density, antioxidant activity and testosterone level in male rats.” Clinical nutrition (Edinburgh, Scotland) vol. 27,2 (2008): 289-96. doi:10.1016/j.clnu.2007.12.006 https://www.clinicalnutritionjournal.com/article/S0261-5614(07)00207-5/fulltext
  27. Mirunalini, S., and M. Krishnaveni. “Therapeutic Potential of Phyllanthus Emblica (Amla): The Ayurvedic Wonder.” Journal of Basic and Clinical Physiology and Pharmacology, vol. 21, no. 1, Jan. 2010, 10.1515/jbcpp.2010.21.1.93; https://pubmed.ncbi.nlm.nih.gov/20506691/
  28. Khanna, Savita, et al. “Supplementation of a Standardized Extract from Phyllanthus Emblica Improves Cardiovascular Risk Factors and Platelet Aggregation in Overweight/Class-1 Obese Adults.” Journal of Medicinal Food, vol. 18, no. 4, Apr. 2015, pp. 415–420, 10.1089/jmf.2014.0178; https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC4390209/
  29. ‌Patil, Poournima, and Suresh Killedar. “Chitosan and Glyceryl Monooleate Nanostructures Containing Gallic Acid Isolated from Amla Fruit: Targeted Delivery System.” Heliyon, vol. 7, no. 3, Mar. 2021, p. e06526, 10.1016/j.heliyon.2021.e06526 https://www.sciencedirect.com/science/article/pii/S2405844021006290
  30. Yan, Xiao et al. “Gallic Acid Attenuates Angiotensin II-Induced Hypertension and Vascular Dysfunction by Inhibiting the Degradation of Endothelial Nitric Oxide Synthase.” Frontiers in pharmacology vol. 11 1121. 22 Jul. 2020, doi:10.3389/fphar.2020.01121 https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/32848742/
  31. Usharani, Pingali, et al. “Effects of Phyllanthus Emblica Extract on Endothelial Dysfunction and Biomarkers of Oxidative Stress in Patients with Type 2 Diabetes Mellitus: A Randomized, Double-Blind, Controlled Study.” Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, vol. 6, 26 July 2013, pp. 275–284, 10.2147/DMSO.S46341; https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC3735284/
  32. Kapoor, Mahendra Parkash, et al. “Clinical Evaluation of Emblica Officinalis Gatertn (Amla) in Healthy Human Subjects: Health Benefits and Safety Results from a Randomized, Double-Blind, Crossover Placebo-Controlled Study.” Contemporary Clinical Trials Communications, vol. 17, Mar. 2020, p. 100499, 10.1016/j.conctc.2019.100499; https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC6926135/
  33. Larrosa, Mar, et al. “Ellagitannins, Ellagic Acid and Vascular Health.” Molecular Aspects of Medicine, vol. 31, no. 6, Dec. 2010, pp. 513–539, 10.1016/j.mam.2010.09.005; https://pubmed.ncbi.nlm.nih.gov/20837052/
  34. Bain, Anthony R et al. “Insufficient sleep is associated with impaired nitric oxide-mediated endothelium-dependent vasodilation.” Atherosclerosis vol. 265 (2017): 41-46. doi:10.1016/j.atherosclerosis.2017.08.001 https://linkinghub.elsevier.com/retrieve/pii/S0021-9150(17)31223-6
  35. Kapás, L et al. “Inhibition of nitric oxide synthesis inhibits rat sleep.” Brain research vol. 664,1-2 (1994): 189-96. doi:10.1016/0006-8993(94)91969-0 https://linkinghub.elsevier.com/retrieve/pii/0006-8993(94)91969-0
  36. Saunders, Bryan, et al. “β-Alanine Supplementation to Improve Exercise Capacity and Performance: A Systematic Review and Meta-Analysis.” British Journal of Sports Medicine, vol. 51, no. 8, 18 Oct. 2016, pp. 658–669; https://bjsm.bmj.com/content/51/8/658.long
  37. Trexler, E.T., Smith-Ryan, A.E., Stout, J.R. et al.; “International society of sports nutrition position stand: Beta-Alanine.”; J Int Soc Sports Nutr 12, 30 (2015); https://jissn.biomedcentral.com/articles/10.1186/s12970-015-0090-y
  38. Dunnett, M., and R. C. Harris. “Influence of Oral ß-Alanine and L-Histidine Supplementation on the Carnosine Content of Thegluteus Medius.” Equine Veterinary Journal, vol. 31, no. S30, July 1999, pp. 499–504, 10.1111/j.2042-3306.1999.tb05273.x; https://pubmed.ncbi.nlm.nih.gov/10659307/
  39. Harris, R. C., et al. “The Absorption of Orally Supplied β-Alanine and Its Effect on Muscle Carnosine Synthesis in Human Vastus Lateralis.” Amino Acids, vol. 30, no. 3, 24 Mar. 2006, pp. 279–289, doi:10.1007/s00726-006-0299-9.; https://pubmed.ncbi.nlm.nih.gov/16554972/
  40. Hobson, R M, et al; “Effects of β-Alanine Supplementation on Exercise Performance: a Meta-Analysis.”; Amino Acids; Springer Vienna; July 2012; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3374095/
  41. Bellinger, Phillip M., and Clare L. Minahan. “The Effect Of β-Alanine Supplementation on Cycling Time Trials of Different Length.” European Journal of Sport Science, vol. 16, no. 7, 11 Dec. 2015, pp. 829–836, 10.1080/17461391.2015.1120782; https://pubmed.ncbi.nlm.nih.gov/26652037/
  42. Hobson, Ruth M., et al. “Effect of Beta-Alanine with and without Sodium Bicarbonate on 2,000-m Rowing Performance.” International Journal of Sport Nutrition and Exercise Metabolism, vol. 23, no. 5, Oct. 2013, pp. 480–487, 10.1123/ijsnem.23.5.480; https://pubmed.ncbi.nlm.nih.gov/23535873/
  43. DE Camargo, Júlio Benvenutti Bueno, et al. “Beta-Alanine Supplementation for Four Weeks Increases Volume Index and Reduces Perceived Effort of Resistance-Trained Men: A Pilot Study.” International Journal of Exercise Science, vol. 14, no. 2, 2021, pp. 994–1003; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439704/
  44. Dolan, Eimear, et al. “A Systematic Risk Assessment and Meta-Analysis on the Use of Oral β-Alanine Supplementation.” Advances in Nutrition, vol. 10, no. 3, 13 Apr. 2019, pp. 452–463, 10.1093/advances/nmy115; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520041/
  45. Pasantes-Morales, H., et al. “Taurine: An Osmolyte in Mammalian Tissues.” Advances in Experimental Medicine and Biology, 1998, pp. 209–217, 10.1007/978-1-4899-0117-0_27; https://link.springer.com/chapter/10.1007/978-1-4899-0117-0_27
  46. Waldron, M., et al. May 2018. “The Effects of an Oral Taurine Dose and Supplementation Period on Endurance Exercise Performance in Humans: A Meta-Analysis.” Sports Medicine vol. 48,5; 1247-53; https://pubmed.ncbi.nlm.nih.gov/29546641
  47. Ibrahim, Marwan A et al. “Therapeutic role of taurine as antioxidant in reducing hypertension risks in rats.” Heliyon vol. 6,1 e03209. 17 Jan. 2020, doi:10.1016/j.heliyon.2020.e03209; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970174/
  48. Jong, Chian Ju et al. “Mechanism underlying the antioxidant activity of taurine: prevention of mitochondrial oxidant production.” Amino acids vol. 42,6 (2012): 2223-32. doi:10.1007/s00726-011-0962-7; https://pubmed.ncbi.nlm.nih.gov/21691752/
  49. Spriet, Lawrence L, and Jamie Whitfield. “Taurine and skeletal muscle function.” Current opinion in clinical nutrition and metabolic care vol. 18,1 (2015): 96-101. doi:10.1097/MCO.0000000000000135; https://pubmed.ncbi.nlm.nih.gov/25415270/
  50. Chen, C. et al. Aug. 2019. “Roles of Taurine in Cognitive Function of Physiology, Pathologies, and Toxication.” Life Sciences vol. 15, 231; https://pubmed.ncbi.nlm.nih.gov/31220527/
  51. Wang, Ke, et al. “Taurine Improves Neuron Injuries and Cognitive Impairment in a Mouse Parkinson’s Disease Model through Inhibition of Microglial Activation.” NeuroToxicology, vol. 83, Mar. 2021, pp. 129–136, 10.1016/j.neuro.2021.01.002; https://www.sciencedirect.com/science/article/abs/pii/S0161813X21000085
  52. Guo, Ying-Ying et al. “Taurine-mediated browning of white adipose tissue is involved in its anti-obesity effect in mice.” The Journal of biological chemistry vol. 294,41 (2019): 15014-15024. doi:10.1074/jbc.RA119.009936; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791308/
  53. Kim, Kyoung Soo et al. “Taurine Stimulates Thermoregulatory Genes in Brown Fat Tissue and Muscle without an Influence on Inguinal White Fat Tissue in a High-Fat Diet-Induced Obese Mouse Model.” Foods (Basel, Switzerland) vol. 9,6 688. 26 May. 2020, doi:10.3390/foods9060688; https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/32466447/
  54. Kim, Kyoung Soo et al. “Anti-obesity effect of taurine through inhibition of adipogenesis in white fat tissue but not in brown fat tissue in a high-fat diet-induced obese mouse model.” Amino acids vol. 51,2 (2019): 245-254. doi:10.1007/s00726-018-2659-7; https://dx.doi.org/10.1007/s00726-018-2659-7
  55. Lin, Shan et al. “Taurine improves obesity-induced inflammatory responses and modulates the unbalanced phenotype of adipose tissue macrophages.” Molecular nutrition & food research vol. 57,12 (2013): 2155-65. doi:10.1002/mnfr.201300150; https://doi.org/10.1002/mnfr.201300150
  56. Chen, Qi et al. “The Dose Response of Taurine on Aerobic and Strength Exercises: A Systematic Review.” Frontiers in physiology vol. 12 700352. 18 Aug. 2021, doi:10.3389/fphys.2021.700352; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419774/
  57. Ripps, H. et al. Nov. 2012. “Review: Taurine: A “Very Essential Amino Acid.” Molecular Vision vol. 18. 2673-86; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501277/
  58. Attipoe, S. et al; Tyrosine for Mitigating Stress and Enhancing Performance in Healthy Adult Humans, a Rapid Evidence Assessment of the Literature; Military Medicine; Volume 180, Issue 7, July 2015, Pages 754–765; https://academic.oup.com/milmed/article/180/7/754/4160625#101253256
  59. Colzato, Lorenza S et al. “Working memory reloaded: tyrosine repletes updating in the N-back task.” Frontiers in behavioral neuroscience vol. 7 200. 16 Dec. 2013, doi:10.3389/fnbeh.2013.00200 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3863934/
  60. Steenbergen, Laura et al. “Tyrosine promotes cognitive flexibility: evidence from proactive vs. reactive control during task switching performance.” Neuropsychologia vol. 69 (2015): 50-5. doi:10.1016/j.neuropsychologia.2015.01.022 https://pubmed.ncbi.nlm.nih.gov/25598314/
  61. Neri, D F et al. “The effects of tyrosine on cognitive performance during extended wakefulness.” Aviation, space, and environmental medicine vol. 66,4 (1995): 313-9. https://linkinghub.elsevier.com/retrieve/pii/S0028-3932(15)00029-9
  62. McAllister, R M et al. “Thyroid status and exercise tolerance. Cardiovascular and metabolic considerations.” Sports medicine (Auckland, N.Z.) vol. 20,3 (1995): 189-98. doi:10.2165/00007256-199520030-00005; https://link.springer.com/article/10.2165/00007256-199520030-00005
  63. Sunita et al. “Heart rate and blood pressure response to exercise and recovery in subclinical hypothyroid patients.” International journal of applied & basic medical research vol. 3,2 (2013): 106-10. doi:10.4103/2229-516X.117076; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3783662/
  64. National Center for Biotechnology Information. “PubChem Pathway Summary for Pathway SMP0000006, Tyrosine Metabolism, Source: PathBank” PubChem, https://pubchem.ncbi.nlm.nih.gov/pathway/PathBank:SMP0000006. Accessed 2 November, 2021.
  65. Khaliq, W et al. “Reductions in tyrosine levels are associated with thyroid hormone and catecholamine disturbances in sepsis.” Intensive Care Medicine Experimental vol. 3,Suppl 1 A686. 1 Oct. 2015, doi:10.1186/2197-425X-3-S1-A686 https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC4798095/
  66. Wadden TA, Mason G, Foster GD, Stunkard AJ, Prange AJ. Effects of a very low calorie diet on weight, thyroid hormones and mood. Int J Obes. 1990 Mar;14(3):249-58; https://pubmed.ncbi.nlm.nih.gov/2341229/
  67. Ciloglu, Figen et al. “Exercise intensity and its effects on thyroid hormones.” Neuro endocrinology letters vol. 26,6 (2005): 830-4; https://pubmed.ncbi.nlm.nih.gov/16380698/
  68. Mullur, Rashmi et al; “Thyroid hormone regulation of metabolism”; Physiological reviews; vol. 94; 2014; 355-82; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4044302/
  69. Glaeser, B.S., et al., Elevation of plasma tyrosine after a single oral dose of L-tyrosine. Life Sci, 1979. 25(3): p. 265-71; https://www.sciencedirect.com/science/article/abs/pii/0024320579902947
  70. Smith ML, Hanley W, Clarke J, et al. Randomised controlled trial of tyrosine supplementation on neuropsychological performance in phenylketonuria. Archives of Disease in Childhood. 1998;78(2):116-121. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1717450/
  71. Pietz J, Landwehr R, Kutscha A, Schmidt H, de Sonneville L, Trefz FK. Effect of high-dose tyrosine supplementation on brain function in adults with phenylketonuria. J Pediatr. 1995;127(6):936-943. https://www.ncbi.nlm.nih.gov/pubmed/8523192
  72. Lykkelund C, Nielsen JB, Lou HC, et al. Increased neurotransmitter biosynthesis in phenylketonuria induced by phenylalanine restriction or by supplementation of unrestricted diet with large amounts of tyrosine. Eur J Pediatr. 1988;148(3):238-245. https://www.ncbi.nlm.nih.gov/pubmed/2463918
  73. Wilkinson DJ, Smeeton NJ, Watt PW. Ammonia metabolism, the brain and fatigue; revisiting the link. Prog Neurobiol. 2010 Jul;91(3):200-19. doi: 10.1016/j.pneurobio.2010.01.012; https://linkinghub.elsevier.com/retrieve/pii/S0301-0082(10)00023-7
  74. Chen, Shu, et al. “Involvement of Ammonia Metabolism in the Improvement of Endurance Performance by Tea Catechins in Mice.” Scientific Reports, vol. 10, no. 1, 8 Apr. 2020, 10.1038/s41598-020-63139-9; https://www.nature.com/articles/s41598-020-63139-9
  75. Suminski, R. R., et al. Acute effect of amino acid ingestion and resistance exercise on plasma growth hormone concentration in young men. International Journal of Sport Nutrition, vol. 7, no. 1, 1997, pp. 48-60. https://journals.humankinetics.com/view/journals/ijsnem/7/1/article-p48.xml
  76. Ho YY, Nakato J, Mizushige T, Kanamoto R, Tanida M, Akiduki S, Ohinata K. l-Ornithine stimulates growth hormone release in a manner dependent on the ghrelin system. Food Funct. 2017 Jun 1;8(6):2110-2114. doi: 10.1039/c7fo00309a; https://pubs.rsc.org/en/content/articlelanding/2017/FO/C7FO00309A
  77. Miyake, Mika et al. “Randomised controlled trial of the effects of L-ornithine on stress markers and sleep quality in healthy workers.” Nutrition journal vol. 13 53. 3 Jun. 2014, doi:10.1186/1475-2891-13-53; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4055948/
  78. Cynober, L et al. “Action of ornithine alpha-ketoglutarate, ornithine hydrochloride, and calcium alpha-ketoglutarate on plasma amino acid and hormonal patterns in healthy subjects.” Journal of the American College of Nutrition vol. 9,1 (1990): 2-12. doi:10.1080/07315724.1990.10720343 https://www.tandfonline.com/doi/abs/10.1080/07315724.1990.10720343
  79. Cynober, Luc. “Ornithine alpha-ketoglutarate as a potent precursor of arginine and nitric oxide: a new job for an old friend.” The Journal of nutrition vol. 134,10 Suppl (2004): 2858S-2862S; discussion 2895S. doi:10.1093/jn/134.10.2858s https://www.sciencedirect.com/science/article/pii/S0022316623031437
  80. Gyanwali, Bibek et al. “Alpha-Ketoglutarate dietary supplementation to improve health in humans.” Trends in endocrinology and metabolism: TEM vol. 33,2 (2022): 136-146. doi:10.1016/j.tem.2021.11.003 https://www.cell.com/trends/endocrinology-metabolism/abstract/S1043-2760(21)00266-6
  81. Saihara K, Kamikubo R, Ikemoto K, Uchida K, Akagawa M; “Pyrroloquinoline Quinone, a Redox-Active o‑Quinone, Stimulates Mitochondrial Biogenesis by Activating the SIRT1PGC-1α Signaling Pathway”; Biochemistry; 2017; 56; 6615−6625; https://pubs.acs.org/doi/10.1021/acs.biochem.7b01185
  82. Harris, Calliandra B, et al; “Dietary Pyrroloquinoline Quinone (PQQ) Alters Indicators of Inflammation and Mitochondrial-Related Metabolism in Human Subjects.”; The Journal of Nutritional Biochemistry; U.S. National Library of Medicine; Dec. 2013; https://www.ncbi.nlm.nih.gov/pubmed/24231099
  83. Rosenmeier, Jaya B et al. “Circulating ATP-induced vasodilatation overrides sympathetic vasoconstrictor activity in human skeletal muscle.” The Journal of physiology vol. 558,Pt 1 (2004): 351-65. doi:10.1113/jphysiol.2004.063107 https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/15155791/
  84. Nakano, Masahiko, et al; “Effects of Antioxidant Supplements (BioPQQ™) on Cerebral Blood Flow and Oxygen Metabolism in the Prefrontal Cortex.”; Advances in Experimental Medicine and Biology; U.S. National Library of Medicine; 2016; https://www.ncbi.nlm.nih.gov/pubmed/27526146
  85. Nakano, M., et al; “Effect of Oral Supplementation with Pyrroloquinoline Quinone on Stress, Fatigue, and Sleep.”; Functional Foods in Health and Disease; 2012; 2(8); 307-324; https://www.functionalfoodscenter.net/files/56592277.pdf
  86. Weaver, Connie M. “Potassium and Health.” Advances in Nutrition, vol. 4, no. 3, 1 May 2013, pp. 368S377S, 10.3945/an.112.003533; https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC3650509/
  87. Fj, He, and MacGregor Ga. “Beneficial Effects of Potassium on Human Health.” Physiologia Plantarum, 1 Aug. 2008; https://pubmed.ncbi.nlm.nih.gov/18724413/
  88. Houston, Mark C. “The Importance of Potassium in Managing Hypertension.” Current Hypertension Reports, vol. 13, no. 4, 15 Mar. 2011, pp. 309–317, 10.1007/s11906-011-0197-8; https://pubmed.ncbi.nlm.nih.gov/21403995/
  89. Drewnowski, Adam, et al. “Reducing the Sodium-Potassium Ratio in the US Diet: A Challenge for Public Health.” The American Journal of Clinical Nutrition, vol. 96, no. 2, 3 July 2012, pp. 439–444, 10.3945/ajcn.111.025353; https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC3396449/
  90. Fulgoni, Victor L., et al. “Foods, Fortificants, and Supplements: Where Do Americans Get Their Nutrients?” The Journal of Nutrition, vol. 141, no. 10, 24 Aug. 2011, pp. 1847–1854, 10.3945/jn.111.142257; https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC3174857/
  91. Maillot, Matthieu, et al. “Food Pattern Modeling Shows That the 2010 Dietary Guidelines for Sodium and Potassium Cannot Be Met Simultaneously.” Nutrition Research (New York, N.y.), vol. 33, no. 3, 1 Mar. 2013, p. 188, 10.1016/j.nutres.2013.01.004; https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC3878634/
  92. Adrogué, Horacio J., and Nicolaos E. Madias. “Sodium and Potassium in the Pathogenesis of Hypertension.” New England Journal of Medicine, vol. 356, no. 19, 10 May 2007, pp. 1966–1978, 10.1056/nejmra064486; https://pubmed.ncbi.nlm.nih.gov/17494929/
  93. Dyer, Alan R., et al. “Urinary Electrolyte Excretion in 24 Hours and Blood Pressure in the INTERSALT Study.” American Journal of Epidemiology, vol. 139, no. 9, 1 May 1994, pp. 940–951, 10.1093/oxfordjournals.aje.a117100; https://www.ncbi.nlm.nih.gov/pubmed/8166144
  94. Elliott, P., et al. “Intersalt Revisited: Further Analyses of 24 Hour Sodium Excretion and Blood Pressure within and across Populations.” BMJ, vol. 312, no. 7041, 18 May 1996, pp. 1249–1253, www.bmj.com/content/312/7041/1249, 10.1136/bmj.312.7041.1249; https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC2351086/
  95. Cook, N. R., et al. “Effect of Change in Sodium Excretion on Change in Blood Pressure Corrected for Measurement Error. The Trials of Hypertension Prevention, Phase I.” American Journal of Epidemiology, vol. 148, no. 5, 1 Sept. 1998, pp. 431–444, 10.1093/oxfordjournals.aje.a009668; https://www.ncbi.nlm.nih.gov/pubmed/9737555
  96. Khaw, K T, and E Barrett-Connor. “The Association between Blood Pressure, Age, and Dietary Sodium and Potassium: A Population Study.” Circulation, vol. 77, no. 1, Jan. 1988, pp. 53–61, 10.1161/01.cir.77.1.53; https://www.ncbi.nlm.nih.gov/pubmed/3257173
  97. Xie, J. X., et al. “The Relationship between Urinary Cations Obtained from the INTERSALT Study and Cerebrovascular Mortality.” Journal of Human Hypertension, vol. 6, no. 1, 1 Feb. 1992, pp. 17–21; https://www.ncbi.nlm.nih.gov/pubmed/1583625
  98. Cook, Nancy R. “Joint Effects of Sodium and Potassium Intake on Subsequent Cardiovascular Disease.” Archives of Internal Medicine, vol. 169, no. 1, 12 Jan. 2009, p. 32, 10.1001/archinternmed.2008.523; https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC2629129/
  99. Lemann, Jacob, et al. “Potassium Administration Increases and Potassium Deprivation Reduces Urinary Calcium Excretion in Healthy Adults.” Kidney International, vol. 39, no. 5, May 1991, pp. 973–983, 10.1038/ki.1991.123; https://pubmed.ncbi.nlm.nih.gov/1648646/
  100. Gregory, Naina Sinha, et al. “Potassium Citrate Decreases Bone Resorption in Postmenopausal Women with Osteopenia: A Randomized, Double-Blind Clinical Trial” Endocrine Practice, vol. 21, no. 12, Dec. 2015, pp. 1380–1386, 10.4158/ep15738.or; https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC5558825/
  101. Strazzullo P., Leclercq C.; “Sodium.” Advanced Nutrition; March 2014; 5(2) 188-190; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951800/
  102. Valentine, V. 2007. “The Importance of Salt in the Athlete’s Diet.” Current Sports Medicine Reports vol. 6,4 (2007): 237-40. https://pubmed.ncbi.nlm.nih.gov/17617999/
  103. Remer, Thomas. “High Salt Intake: Detrimental Not Only for Blood Pressure, but Also for Bone Health?” Endocrine, vol. 49, no. 3, 10 May 2015, pp. 580–582, 10.1007/s12020-015-0626-6. Accessed 13 July 2021. https://link.springer.com/article/10.1007/s12020-015-0626-6
  104. Hooper L, Martin N, Jimoh OF, Kirk C, Foster E, Abdelhamid AS. Reduction in saturated fat intake for cardiovascular disease. Cochrane Database Syst Rev. 2020;8(8):CD011737. 2020 Aug 21. doi:10.1002/14651858.CD011737.pub3; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092457/
  105. O’Donnell MJ, Yusuf S, Mente A, Gao P, Mann JF, Teo K, McQueen M, Sleight P, Sharma AM, Dans A, Probstfield J, Schmieder RE. Urinary sodium and potassium excretion and risk of cardiovascular events. JAMA. 2011 Nov 23;306(20):2229-38. doi: 10.1001/jama.2011.1729; https://pubmed.ncbi.nlm.nih.gov/22110105/
  106. Hernandez-Vazquez AJ, Garcia-Sanchez JA, Moreno-Arriola E, Salvador-Adriano A, Ortega-Cuellar D, Velazquez-Arellano A. Thiamine Deprivation Produces a Liver ATP Deficit and Metabolic and Genomic Effects in Mice: Findings Are Parallel to Those of Biotin Deficiency and Have Implications for Energy Disorders. J Nutrigenet Nutrigenomics. 2016;9(5-6):287-299. doi: 10.1159/000456663. Epub 2017 Feb 18. PMID: 28214879. https://pubmed.ncbi.nlm.nih.gov/28214879/
  107. Zubaran, C et al. “Wernicke-Korsakoff syndrome.” Postgraduate medical journal vol. 73,855 (1997): 27-31. doi:10.1136/pgmj.73.855.27 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2431190/
  108. Lonsdale D. Thiamin(e): the spark of life. Subcell Biochem. 2012;56:199-227. doi: 10.1007/978-94-007-2199-9_11. PMID: 22116701. https://pubmed.ncbi.nlm.nih.gov/22116701/
  109. Alaei Shahmiri F, Soares MJ, Zhao Y, Sherriff J. High-dose thiamine supplementation improves glucose tolerance in hyperglycemic individuals: a randomized, double-blind cross-over trial. Eur J Nutr. 2013 Oct;52(7):1821-4. doi: 10.1007/s00394-013-0534-6. Epub 2013 May 29. PMID: 23715873. https://pubmed.ncbi.nlm.nih.gov/23715873/
  110. DiNicolantonio JJ, Niazi AK, Lavie CJ, O’Keefe JH, Ventura HO. Thiamine supplementation for the treatment of heart failure: a review of the literature. Congest Heart Fail. 2013 Jul-Aug;19(4):214-22. doi: 10.1111/chf.12037. PMID: 23910704. https://pubmed.ncbi.nlm.nih.gov/23910704/
  111. Prinz-Langenohl, R et al; “[6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C–>T polymorphism of methylenetetrahydrofolate reductase.”; British journal of pharmacology; vol. 158,8; 2009; 2014-21; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2807663/
  112. Pietrzik, Klaus, et al; “Folic Acid and L-5-Methyltetrahydrofolate: Comparison of Clinical Pharmacokinetics and Pharmacodynamics.”; Clinical Pharmacokinetics; U.S. National Library of Medicine; Aug. 2010; https://www.ncbi.nlm.nih.gov/pubmed/20608755
  113. Knowles, L et al. “Treatment with Mefolinate (5-Methyltetrahydrofolate), but Not Folic Acid or Folinic Acid, Leads to Measurable 5-Methyltetrahydrofolate in Cerebrospinal Fluid in Methylenetetrahydrofolate Reductase Deficiency.” JIMD reports vol. 29 (2016): 103-107. doi:10.1007/8904_2016_529 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5059208/
  114. Wierzbicki, Anthony S; “Homocysteine and Cardiovascular Disease: a Review of the Evidence.”; Diabetes & Vascular Disease Research; U.S. National Library of Medicine; June 2007; https://www.ncbi.nlm.nih.gov/pubmed/17654449
  115. Casas, J P, et al; “Homocysteine and Stroke: Evidence on a Causal Link from Mendelian Randomisation.”; Lancet (London, England);, U.S. National Library of Medicine; https://www.ncbi.nlm.nih.gov/pubmed/15652605
  116. Czeizel, Andrew E et al; “Folate deficiency and folic acid supplementation: the prevention of neural-tube defects and congenital heart defects.”; Nutrients; vol. 5,11; 4760-75; 21 Nov. 2013; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847759/
  117. Choi, Sang-Woon, and Joel B Mason; “Folate Status: Effects on Pathways of Colorectal Carcinogenesis.”; The Journal of Nutrition; U.S. National Library of Medicine; Aug. 2002; https://www.ncbi.nlm.nih.gov/pubmed/12163703
  118. Gupta, A et al. “High homocysteine, low folate, and low vitamin B6 concentrations: prevalent risk factors for vascular disease in heart transplant recipients.” Transplantation vol. 65,4 (1998): 544-50. doi:10.1097/00007890-199802270-00016 https://journals.lww.com/transplantjournal/Fulltext/1998/02270/HIGH_HOMOCYSTEINE,_LOW_FOLATE,_AND_LOW_VITAMIN_B6.16.aspx
  119. Spellicy, Catherine J et al. “The MTHFR C677T Variant is Associated with Responsiveness to Disulfiram Treatment for Cocaine Dependency.” Frontiers in psychiatry vol. 3 109. 14 Jan. 2013, doi:10.3389/fpsyt.2012.00109. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3544007/
  120. Chita, Dana Simona et al. “MTHFR Gene Polymorphisms Prevalence and Cardiovascular Risk Factors Involved in Cardioembolic Stroke Type and Severity.” Brain sciences vol. 10,8 476. 24 Jul. 2020, doi:10.3390/brainsci10080476. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463445/
  121. Venn, Bernard J, et al; “Comparison of the Effect of Low-Dose Supplementation with L-5-Methyltetrahydrofolate or Folic Acid on Plasma Homocysteine: a Randomized Placebo-Controlled Study.”; The American Journal of Clinical Nutrition; U.S. National Library of Medicine; Mar. 2003; https://www.ncbi.nlm.nih.gov/pubmed/12600857
  122. Shelton, Richard C et al; “Assessing Effects of l-Methylfolate: Results of a Real-World Patient Experience Trial.”; The primary care companion for CNS disorders; vol. 15,4; 2013; PCC.13m01520; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869616/
  123. Anderson, Shanna et al; “Anxiety and Methylenetetrahydrofolate Reductase Mutation Treated With S-Adenosyl Methionine and Methylated B Vitamins.”; Integrative medicine (Encinitas, Calif.); vol. 15,2; 2016; 48-52; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4898281/
  124. Shorter KR, Felder MR, Vrana PB. Consequences of dietary methyl donor supplements: Is more always better? Prog Biophys Mol Biol. 2015 Jul;118(1-2):14-20. doi: 10.1016/j.pbiomolbio.2015.03.007. Epub 2015 Apr 2. PMID: 25841986. https://linkinghub.elsevier.com/retrieve/pii/S0079-6107(15)00043-7
  125. da Silva, Weslay Rodrigues et al. “Recognition and management of vitamin B12 deficiency: Report of four cases with oral manifestations.” Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry vol. 42,4 (2022): 410-415. doi:10.1111/scd.12685 https://onlinelibrary.wiley.com/doi/10.1111/scd.12685
  126. Langan, Robert C, and Andrew J Goodbred. “Vitamin B12 Deficiency: Recognition and Management.” American family physician vol. 96,6 (2017): 384-389. https://www.aafp.org/pubs/afp/issues/2017/0915/p384.html
  127. Wahbeh, Farah, and Mange Manyama. “The role of Vitamin B12 and genetic risk factors in the etiology of neural tube defects: A systematic review.” International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience vol. 81,5 (2021): 386-406. doi:10.1002/jdn.10113. https://onlinelibrary.wiley.com/doi/10.1002/jdn.10113
  128. Rogne, Tormod et al. “Associations of Maternal Vitamin B12 Concentration in Pregnancy With the Risks of Preterm Birth and Low Birth Weight: A Systematic Review and Meta-Analysis of Individual Participant Data.” American journal of epidemiology vol. 185,3 (2017): 212-223. doi:10.1093/aje/kww212 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5390862/
  129. ‌Bala, Renu et al. “Hyperhomocysteinemia and low vitamin B12 are associated with the risk of early pregnancy loss: A clinical study and meta-analyses.” Nutrition research (New York, N.Y.) vol. 91 (2021): 57-66. doi:10.1016/j.nutres.2021.05.002. https://linkinghub.elsevier.com/retrieve/pii/S0271-5317(21)00023-3
  130. Gröber, Uwe et al. “Neuroenhancement with vitamin B12-underestimated neurological significance.” Nutrients vol. 5,12 5031-45. 12 Dec. 2013, doi:10.3390/nu5125031. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3875920/
  131. Köbe, Theresa et al. “Vitamin B-12 concentration, memory performance, and hippocampal structure in patients with mild cognitive impairment.” The American journal of clinical nutrition vol. 103,4 (2016): 1045-54. doi:10.3945/ajcn.115.116970 https://www.sciencedirect.com/science/article/pii/S0002916523119289
  132. Ankar, Alex, and Anil Kumar. “Vitamin B12 Deficiency (Cobalamin).” Nih.gov, StatPearls Publishing, 2019, www.ncbi.nlm.nih.gov/books/NBK441923/
  133. Chiovato, Luca et al. “Hypothyroidism in Context: Where We’ve Been and Where We’re Going.” Advances in therapy vol. 36,Suppl 2 (2019): 47-58. doi:10.1007/s12325-019-01080-8 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822815/
  134. Pearce, Elizabeth N. “Is Iodine Deficiency Reemerging in the United States?” AACE Clinical Case Reports, vol. 1, no. 1, 2015, pp. e81–e82, 10.4158/ep14472.co; https://www.sciencedirect.com/science/article/pii/S2376060520303680
  135. Aggrawal, Manali, and Jeffrey Scott Rohrer. “Selective and Sensitive Determination of Bromate in Bread by Ion Chromatography-Mass Spectrometry.” Journal of Chromatography. A, vol. 1615, 29 Mar. 2020, p. 460765, 10.1016/j.chroma.2019.460765; https://pubmed.ncbi.nlm.nih.gov/31848031/
  136. Zava, Theodore T, and David T Zava. “Assessment of Japanese Iodine Intake Based on Seaweed Consumption in Japan: A Literature-Based Analysis.” Thyroid Research, vol. 4, no. 1, 2011, p. 14, 10.1186/1756-6614-4-14; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3204293/
  137. Singh, Navneet, et al. “A Comparative Study of Fluoride Ingestion Levels, Serum Thyroid Hormone & TSH Level Derangements, Dental Fluorosis Status among School Children from Endemic and Non-Endemic Fluorosis Areas.” SpringerPlus, vol. 3, 3 Jan. 2014, doi:10.1186/2193-1801-3-7; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890436/
  138. Han, Jianlin, et al. “Chemical Aspects of Human and Environmental Overload with Fluorine.” Chemical Reviews, vol. 121, no. 8, 16 Mar. 2021, pp. 4678–4742, doi:10.1021/acs.chemrev.0c01263; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8945431/
  139. Malin AJ, Riddell J, McCague H, Till C. Fluoride exposure and thyroid function among adults living in Canada: Effect modification by iodine status. Environ Int. 2018 Dec;121(Pt 1):667-674. doi: 10.1016/j.envint.2018.09.026. Epub 2018 Oct 10. PMID: 30316182. https://pubmed.ncbi.nlm.nih.gov/30316182/
  140. Buchberger W, Holler W, Winsauer K. Effects of sodium bromide on the biosynthesis of thyroid hormones and brominated/iodinated thyronines. J Trace Elem Electrolytes Health Dis. 1990 Mar;4(1):25-30. PMID: 2135954. https://pubmed.ncbi.nlm.nih.gov/2135954/
  141. Chung, Hye Rim. “Iodine and thyroid function.” Annals of pediatric endocrinology & metabolism vol. 19,1 (2014): 8-12. doi:10.6065/apem.2014.19.1.8 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049553/
  142. “Thyroxine | Hormone Health Network.”; Hormone.org; https://www.hormone.org/hormones-and-health/hormones/thyroxine
  143. Danforth, J r, and A Burger; “The Role of Thyroid Hormones in the Control of Energy Expenditure.”; Current Neurology and Neuroscience Reports.; U.S. National Library of Medicine; Nov. 1984; https://www.ncbi.nlm.nih.gov/pubmed/6391756
  144. Chaker, Layal et al. “Thyroid function and risk of type 2 diabetes: a population-based prospective cohort study.” BMC medicine vol. 14,1 150. 30 Sep. 2016, doi:10.1186/s12916-016-0693-4; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043536/
  145. Zhang, Yun et al. “Association between Hyperhomocysteinemia and Thyroid Hormones in Euthyroid Diabetic Subjects.” BioMed research international vol. 2015 (2015): 196379. doi:10.1155/2015/196379; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4491378/
  146. Mahanta, Anindita, et al; “Prevalence of Hypothyroidism in Assam: A Clinic-Based Observational Study.”; Thyroid Research and Practice; vol. 14, no. 2; 2017; p. 63; http://www.thetrp.net/article.asp?issn=0973-0354%3Byear%3D2017%3Bvolume%3D14%3Bissue%3D2%3Bspage%3D63%3Bepage%3D70%3Baulast%3DMahanta
  147. Silva, J E; “The multiple contributions of thyroid hormone to heat production”; Journal of clinical investigation; vol. 108,1; 2001; 35-7; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC209345/
  148. Kim, Matthew I; “Hypothyroidism in the Elderly.”; Current Neurology and Neuroscience Reports; U.S. National Library of Medicine; 15 Mar. 2017; https://www.ncbi.nlm.nih.gov/books/NBK279005/
  149. Cooke, G E, et al; “Hippocampal Volume Is Decreased in Adults with Hypothyroidism.”; Current Neurology and Neuroscience Reports; U.S. National Library of Medicine; Mar. 2014; https://www.ncbi.nlm.nih.gov/pubmed/24205791

Comments and Discussion (Powered by the PricePlow Forum)