“Presenting Scientific Research for Optimization of Everyday Life"

A Non-Stimulant Based Formula Designed for Blood-flow & Hydration

September 09, 2022

A simple stroll around any grocery store or convenience store can overwhelm a customer looking for a hydrating beverage. There are beverages labeled “energizing” and "hydrating,” which oftentimes do not align with the nutritional facts. As a user of many of these products, I can attest that the market's opportunities for profiteering and its customers' lack of education make this product line flawed. Certain products contain certain promising ingredients. Unfortunately, these ingredients are at sub-efficacious dosages, and unless a consumer is purchasing multiple beverages a day, they are not reaping the benefits claimed by the product. The aim of this blog post is to formulate a product with efficacious dosages as well as include ingredients that are proven to increase hydration. This formulation is a combination of unique products that a consumer may not want to buy separately. 
Formulation Rationale
The ingredients in this formula will be explained one by one, with information regarding their mechanism of action and their effectiveness in various clinical trials and in vivo studies. As a formula that will include a variety of ingredients, the interactive effects of those ingredients will also be explained. This product formula is not meant to replace a nutrient-dense diet, supplement protocol, or adequate water intake. However, it is intended to be consumed to improve hydration that may have been impaired via hard exercise or a long-work day. While this product is labeled as a hydration enhancer, it will include ingredients known to maintain ATP production,  increase intramuscular hydration, and vasodilation. This product's formula will not include stimulants, including caffeine. This is because a single serving a day is intended, and this may not be sustainable if stimulants are included. In conjunction with the previous rationale, this product is intended for use at any time of the day; therefore, a nighttime administration should not contain any amount of caffeine. In the future, a peri-workout formula will be designed and it is intended that on days where the stimulant-based pre-workout formula is not being consumed, this formula will be. 
Ingredients & Rationale
Creatine Monohydrate
Creatine monohydrate is a well-known supplement in the fitness industry. It is commonly included in pre-workout formulas that are well-designed. However, with an increasing number of suboptimal pre-workout supplements available the recommended intake of 5,000 mg may not be met. An efficacious dose of creatine can be taken at any time of the day and not negatively impact the quality of sleep.
Mechanisms of Action
Creatine has a major impact on energy metabolism, mainly through its effects on adenosine triphosphate (ATP). ATP is a form of energy found throughout the body. It is most commonly produced at the end of the electron transport chain and ATP synthase found in the mitochondria. ATP functions as a form of energy by phosphorylating enzymes, thus activating them, or ATP can be converted to ADP directly by ATP hydrolysis. When this occurs, since the bond between the gamma and beta phosphate groups is a high-energy bond, when it is broken, energy is released and this can be captured by machinery in the cell. In the body, there are often times when the body is under hypoxic conditions, such as during anaerobic exercise. Under these low oxygen conditions, the cell cannot use oxidative phosphorylation, which is the process of creating ATP from ADP in the mitochondria. Since there is low oxygen, the cell can use other mechanisms to create energy, such as lactic acid metabolism or creatine kinase phosphorylation. 
Creatine acts to alter ATP availability through the enzyme creatine kinase, which takes the gamma phosphate from ATP and transfers it to creatine, thus resulting in phosphorylated creatine, or PCr. This PCr moves out of the mitochondria and into the cytosol. This is useful for two reasons. Since PCr is polarized, it cannot freely diffuse out of the cell, so the cell retains the PCr molecule. Another reason this is useful is that when ATP is needed during exercise, lactic acid is produced, which decreases the pH in the cell. This pH drop allows PCr to donate its phosphate group to an adenosine diphosphate (ADP) molecule. This donation of a phosphate group turns the ADP molecule into an ATP which is now available as an energy source for the cell. Since PCr was able to move into the cytosol, the ATP produced from its breakdown is already located in a primary location for viability. 
Creatine also influences protein synthesis via the mammalian target of rapamycin pathway. During a fasted state, where the body is breaking down proteins into their fundamental amino acids and using them to create glucose as fuel, creatine supplementation increases protein accumulation in skeletal muscle cells. This alleviates muscle catabolism due to fasting and caloric restriction. The mechanism by which creatine does this is by inhibiting the ubiquitin-proteasome pathway. The ubiquitin-proteasome pathway is involved in degrading proteins. Creatine is also safe to use at recommended dosages and does not influence the hypothalamus-pituitary-gonads axis, so it will not influence testosterone or dihydrotestosterone. 
Creatine & Water Retention
Creatine is an osmotic agent, which means creatine influences osmosis, or the passive movement of water. Since water cannot be actively transported, that is, cannot be moved from an area of low to high concentration using energy, it only flows from low to high solute concentration. To simplify this, since the cell membrane acts as a barrier to prevent the flow of ions, let the example be that the extracellular space is high in solutes, and the intracellular space is low in solutes. In this example, water would flow out of the cell and into the extracellular space, so there would be less water in the cell but the solute concentrations would equilibrate. Since creatine is an osmotic agent, it acts to influence the movement of water in such a way that increased cellular creatine leads to increased water retention. This is due to the transporter of creatine, which is a sodium-dependent transporter. So sodium is required to bring creatine into the cell, which raises intracellular sodium. However, since several transporters bring sodium into the cell, once homeostasis is achieved via expression of sodium channels etc., water retention in the skeletal muscle cell will drop. Although there are studies supporting creatine’s ability to raise total body water content, there are more recent studies disproving water accumulation due to creatine supplementation once homeostasis has been achieved.
Due to unsupported studies and bioscience, it is believed that creatine must be loaded. That is, for the first ten days, a bolus dosage of 10 g must be consumed daily for ten days. After the ten days, an efficacious dose of 5 g/day is recommended. However, recent studies have deemed the loading phase unnecessary and starting with 5 g/day yields equivalent outcomes after a long-term dosing regimen. With that being said, an efficacious dose of 5 g/day is recommended. 
Magnesium is an essential mineral, contributing as a cofactor in more than 300 enzymatic reactions, including the stabilization of ATP. As a cationic mineral, it plays a vital role in regulating calcium, sodium, and potassium. Therefore, during prolonged exercise, athletes may need to increase their magnesium intake due to increased usage and excretion. With that being said, magnesium is found in many formulations, including magnesium citrate, magnesium glycinate, and magnesium threonate. These different formulations are used for a variety of different issues, including magnesium citrate or magnesium oxide for constipation and magnesium threonate for depression. 
In this scenario, magnesium can be helpful in a variety of ways. One of these ways includes inducing vasodilation, or the dilating of the blood vessels. Vasodilation would be beneficial because, firstly, it lowers blood pressure. A lower blood pressure mitigates stress-induced hypertension, which may have resulted from exercise or stress. Secondly, vasodilation allows more nutrients to be shuttled throughout the body. More nutrients will positively impact the cell’s viability. Magnesium chloride at 382 mg/day for 16 weeks was able to reduce symptoms associated with metabolic syndrome. The study found that magnesium significantly reduced blood pressure, fasting triglycerides, and fasting glucose. Another study found that magnesium is effective at lowering insulin resistance, supporting its usage as a possible combination therapy with metformin in managing type 2 diabetes mellitus. 
According to randomized trials, the effects of magnesium on sleep are quite controversial. However, there are observational studies that support its use for improving sleep quality. Magnesium threonate is a relatively new formulation of magnesium that is able to cross the blood-brain barrier more efficiently than other forms of magnesium. It has been shown in many in vivo rodent studies to protect the brain from inflammation and cognitive impairment. Magnesium supplements also play a role in digestion, making it a crucial mineral for proper peristaltic contractions and gut microbiota health. The use of magnesium in a hydration mix is to retain sodium in the body. Since sodium draws water, the use of magnesium indirectly increases sodium retention and therefore water retention. 
Dosage and formulation
To achieve an efficacious dose of magnesium, considering that dietary intake is sufficient, elemental magnesium from this hydration mix should be around 200 mg. To further break down magnesium content, it shall be split into two 100 mg formulations. 100 mg of magnesium glycinate and 100 mg of magnesium threonate, where 100 mg of each is the amount of elemental magnesium in the mix. 
Vitamin B6
Vitamin B6, or pyroxidine, is a water-soluble vitamin involved in over 140 reactions. This vitamin plays many roles throughout the body, including antioxidant homeostasis, and in combination with magnesium, alleviates symptoms of stress. The goal of adding vitamin B6 to this formula is to obtain an additional stress resilience effect due to the combination of B6 and magnesium. Being resilient to stress has massive benefits for one’s mental and physical health. Vasopressin, or anti-diuretic hormone release, is increased during stress, which can lead to extra water retention. However, this can cause a rise in blood pressure and have harmful effects on the cardiovascular system. 
Since vitamin B6 plays a small role in this formula, the dosage will be set at 30 mg. A study found that stress resilience was increased in a group supplemented with 30 mg of vitamin B6 and 300 mg of magnesium. There have been studies implementing vitamin B6 with cancer at higher dosages. 
Vitamin B12
Vitamin B12, or cobalamin, is another water-soluble involved in neurological and hematological regulation pathways. For example, cobalamin is required for DNA synthesis. This is because cobalamin stabilizes the centromere region, thus allowing it to be accessible to machinery. Cobalamin also allows for important epigenetic modifications to the DNA as well, such that cobalamin is required to convert 5-methyl THF into THF and methionine. Downstream, this methionine, an amino acid, is converted to SAM, a methyl donor, which adds methyl groups to DNA. These methyl groups ultimately influence gene expression and protein abundance. Since while working or exercising, the body is burning fuel, DNA synthesis is required, especially during cardiovascular exercise. Since the muscles require more oxygen, cells in the kidney can sense this hypoxia and produce the hormone erythropoietin, which travels through the blood to act on the bone marrow. Erythropoietin stimulates red blood cells in the bone marrow to become mature red blood cells. In order to reach homeostasis, the bone marrow requires DNA synthesis to create normal red blood cells, thus B12 is required. If there isn’t enough cobalamin available, this can result in macrocytic anemia, or the loss of healthy red blood cells and an abnormal phenotype caused by a lack of DNA synthesis due to B12 deficiency. 
Many studies conclude that vitamin B12 is also an important neurological regulator and, as such, vitamin B12 supplementation in combination with antidepressants improves symptoms of depression more than antidepressants alone. This may be due to increased erythrocyte synthesis, which allows the brain to have access to more oxygen, or it may be due to the effects of B12 on energy metabolism. Since neurons prefer to use fatty acids as fuel when glucose is not abundant, during hard exercise, the brain must switch its fuel source. B12 plays a crucial role in catalyzing the reaction of methylmalonyl-CoA into succinyl-CoA. This reaction is crucial in oxidizing fatty acids for energy use. There are many reasons that suggest cobalamin is useful for performance and overall well-being, therefore its inclusion in the formula is crucial.

The recommended daily intake of cobalamin is 2.4 mcg, which is usually attained through diet. Assuming a solid nutritional plan is being followed, methylcobalamin supplementation at 300-500 mcg is optimal. There are studies using upwards of 2000 mcg without reports of any adverse effects. Most energy drinks, hydration formulas, and other blends are oftentimes under 10 mcg, which is not supported by the literature as an efficacious dose.  
Betaine is an N-methylated form of glycine that has increasing evidence to improve a variety of parameters in humans. Betaine has three main roles in the body. First, it acts as a methyl donor to methionine, which can increase creatine synthesis in skeletal muscle. As previously discussed, creatine has an important role in energy homeostasis, such that an increase in creatine leads to accelerated ATP regeneration. Secondly, betaine acts as an osmotic regulator, such that the molecule is able to retain intracellular water. Lastly, betaine is known to substantially increase nitric oxide production, which can lead to vasodilation. Vasodilation allows more nutrients to be shuttled from the gut into muscles and the brain. Interestingly, betaine supplementation at only 2 g/day for 14 weeks significantly increased testosterone in young soccer players. However, whether this was due to increased exercise during the season is unknown. Another study demonstrated that betaine supplementation was able to increase stress resilience. The last known benefit of betaine supplementation is, that supplementation prevents the build-up of homocysteine levels. Altogether, betaine supplementation has been shown to be a promising tool to increase muscle hydration, vasodilation, and energy metabolism. 
Betaine has been shown to be effective at doses ranging from 2.5 g/day to 6 g/day. Some studies have shown supplementation of betaine at >4 g/day can increase total cholesterol levels. Therefore, this formulation will include 3 g/day.
ATP Disodium
Adenosine-5’-triphosphate (ATP) is a commonly found molecule that is involved in a variety of physiological processes. ATP plays a critical role in energy metabolism such that cleaving the gamma phosphate off of ATP into ADP provides lots of energy. This transfer of phosphate can also activate or deactivate certain exercises, which is commonly referred to as phosphorylation. Supplementing ATP disodium is fairly novel when trying to positively impact exercise performance. Oral ATP disodium increases vasodilation and muscle contractility, which can positively impact the feeling of well-being. For these reasons, ATP disodium at 200-400 mg will be included in the formula. 
Honorary Mentions - Other Molecules
Zinc, as highlighted in a recent paper (Zinc), has an important role in the body. However, the point of this formula is to provide a unique combination of molecules to fuel your body. Supplementation with zinc is commonly taken as solid tablets, and including it in this formula would alter that supplementation protocol.  For formulas with zinc included, the dose is oftentimes extremely low, so there is no need to include it in this formula because it should be supplemented separately already. 
Sodium is an important player in water homeostasis. However, a large intake of sodium can negatively impact this regulation. Sodium should be properly measured and taken in the form of iodized salt in order to maintain iodine levels. However, a small dose of sodium, around 300-500mg of sodium, will be included in this formula. The reason for this is two-fold. Firstly, creatine monohydrate is better absorbed in the presence of electrolytes, and secondly, sodium provides a palatable taste to the formulation.
The last molecule to be present is potassium. Since I previously mentioned that creatine is better absorbed in the presence of electrolytes, potassium will be included in this formula. Potassium is central to ion homeostasis and neuronal signaling. Since it is expected that customers of this formula consume an adequate amount of potassium through food intake, a small but effective dose of 200-300 mg will be included in this formula. 

Concluding Remarks
The full formula consists of nine separate ingredients with bounds of literature to support their efficacy. This formula is not meant to replace dietary intake of vitamins but rather an add-on to RDI values. This formula is not designed to increase performance, act as a nootropic, or as a stimulant. In fact, this formula provides nine key elements that can be taken over a long period of time and do not interfere with other energy formulas. This formula is intended to be taken on days that the opti-pre-workout formula is not consumed. The full formula is listed below.  
  • Creatine monohydrate at 5,000 mg
  • Magnesium Threonate at 100 mg
  • Magnesium Glycinate at 100 mg
  • Vitamin B6 at 30 mg
  • Methylcobalamin at 350 mcg
  • Betaine at 3 g 
  • Sodium 300-500 mg
  • Potassium 100 -250 mg
  • ATP disodium at 200-400 mg


Meet The Author

Hello everyone, 

My name is Joshua Giblin. I am a post-bachelor researcher/research technician at USC. My interests range from nutrition to nanomedicine and also practical science to improve everyday life. Through this blog, I aim to communicate practical scientific research and present it to curious individuals so that an educated decision can be made. Thank you for reading the blog and showing your support. 
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