Creatine: Boosting Muscles and Increasing Brain Power

Key takeaways:
~ Creatine acts as a backup energy source for muscles and the brain to use in times of stress.
~ Genetic variants in the genes related to creatine synthesis can impact muscle pain, athletic performance, and cognitive ability.
~ Creatine supplements are inexpensive and readily available. Studies show that creatine monohydrate supplementation effectively boosts muscle power and brain creatine levels under certain conditions.

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What is creatine?

Creatine is an amino acid that plays an important role in energy production within both brain tissue and muscles. The body can synthesize creatine from other amino acids, and you can get it from your diet.

Let’s first take a look at how creatine is used in cellular energy:

Adenosine triphosphate (ATP) is at the heart of cellular energy. ATP is primarily produced in mitochondria — you know, the powerhouse of the cell.

ATP stores energy in the bonds between the phosphates, which store and then can release energy within the cell.

The ‘triphosphate’ part of ATP means it has three phosphates bound together. When ATP releases energy, it sheds one of its phosphates and becomes adenosine diphosphate (ADP) with only two phosphates remaining. This is where creatine comes in. In specific cell types, creatine helps recycle ADP back into ATP by donating a phosphate group. Thus, creatine can help replenish cellular energy when it’s running low.

How does the body make creatine?

While creatine supplements are typically associated with bodybuilders, it is actually utilized in all types of muscles and in the brain.

Creatine is synthesized from the amino acids glycine and arginine, along with a methyl group donated by SAMe.

The biosynthesis of creatine is a multi-step process.

First, glycine and arginine, two common amino acids, combine to form guanidinoacetate. Then, creatine is formed from guanidinoacetate with the addition of a methyl group. This process occurs primarily in the liver and kidneys. Once synthesized, creatine then enters the bloodstream and can be used throughout the body.[ref]

Within cells, creatine can be further converted to phosphocreatine with the help of the enzyme creatine kinase (CK). Phosphocreatine, also known as creatine phosphate, stands ready, available for converting ADP to ATP when more energy is needed.

Muscle cells and the brain both need a lot of ATP for energy. When a lot of energy is required, such as lifting something heavy or sprinting, phosphocreatine rapidly replenishes ATP from ADP. In normal, lower-energy situations, ATP is produced directly from glucose or fatty acids.

In addition to being synthesized in the liver, creatine can be obtained from the diet as well as from supplements. Creatine is naturally found in animal protein-rich foods, such as muscle meats. Supplemental creatine, which bodybuilders commonly use, is also a source of creatine for creating the phosphocreatine used when repairing and building muscles.

Diving deeper into creatine kinase:

I mentioned above that creatine kinase is the enzyme used to convert creatine to phosphocreatine, which can then be used by cells for energy when needed.

There are two types of creatine kinase – mitochondrial and cytosolic – found in the muscle and brain. The phosphocreatine created in the reaction acts as an energy buffer, readily available when muscle cells are stressed and need a burst of ATP for energy.[ref]

In medical contexts, doctors often measure creatine kinase levels in the blood to assess tissue damage, especially in cases like cardiac muscle damage during a heart attack. When tissues are harmed, creatine kinase can leak into the bloodstream, serving as a valuable indicator.

Lab tests for creatine kinase:

Doctors often measure creatine kinase levels in the blood to assess tissue damage. For example, if cardiac muscle is damaged during a heart attack, creatine kinase levels will usually be elevated.[ref] CK levels increase in response to brain, heart, or muscle damage.[ref]

What else elevates creatine kinase (CK) levels on tests?
Aside from heart attacks, strenuous exercise can elevate CK levels up to 15 times the normal level. For instance, after running a marathon, CK levels peak after 24 hours and remain elevated for a week.[ref]

Additional causes of elevated CK levels:

• Statins can raise CK levels in people who have statin-induced muscle pain.[ref]
• Obesity or African ancestry is associated with higher CK levels.[ref]

Creatine and Brain Function:

The brain, despite its relatively small size, uses up a ton of energy (ATP) in comparison with the rest of the body.

In the brain, creatine serves as an energy buffer to provide energy in times of stress.[ref] Genetic mutations that cause creatine deficiency in the brain result in severe developmental disorders and seizures.

Creatine obtained from diet or supplements can cross the blood-brain barrier, but the amount that reaches the brain is generally less than what is absorbed by muscles. This implies that to positively impact brain function, a higher intake of creatine might be necessary. Alternatively, it could mean that creatine is prioritized by the muscles unless there is an urgent requirement for it to go to the brain.

As one research study puts it: “It could be that the brain relies primarily on endogenous creatine synthesis until there is some sort of challenge to brain creatine status. These challenges, which could cause a decrease in brain creatine, could be acute (e.g., sleep deprivation, intense exercise) or chronic (e.g., aging, traumatic brain injury, depression, Alzheimer’s disease, creatine synthesis enzyme deficiencies).”[ref]

Creatine and the Methylation Cycle:

The methylation cycle is a cellular process for producing methyl groups (a carbon + 3 hydrogen atoms) for use in many types of biochemical reactions. Both folate and choline are key contributors of methyl groups in the methylation cycle.

I mentioned above that one step in creatine biosynthesis includes a methyl group. A significant portion of the body’s methyl groups – about 40% – is dedicated to producing creatine.[ref]

When methyl groups are low, homocysteine levels often will be elevated. High homocysteine is linked to an elevated risk of heart problems.

Related article: Homocysteine, heart health, and more

A placebo-controlled clinical trial involving individuals engaged in resistance training showed that creatine supplementation over eight weeks reduced homocysteine levels. The study used an initial dose of 25 g/d of creatine for the first five days, followed by 5 g/day for the rest of the trial.[ref]

Methyl groups also play a role in detoxification processes, including arsenic detoxification. A study found that in people with suboptimal intake of choline or folate, supplementing with creatine or folic acid helps aid the detox reaction for arsenic.[ref]

What happens if you don’t get creatine in your diet?

Creatine is not considered an essential amino acid, meaning you can make it in your body and don’t always have to get it for food.

However, getting creatine in your diet may prevent problems as you age or in times of physical stress.

A study of people over age 65 found that getting less than 1g of creatine via diet each day resulted in more than double the risk of angina (chest pain) and 2.5x the risk of liver problems.

The authors of the study concluded: “The considerable shortage of dietary creatine is associated with an increased risk of heart and liver conditions, which calls for public measures that foster diets rich in creatine-containing foods, and additional research to investigate the role of creatine in age-related diseases.”[ref]

Another study found that getting over 0.95g of creatine in foods daily was protective against cognitive decline in older adults.[ref]

Clinical trials using creatine supplements:

Creatine supplements have been very well studied, with thousands of clinical trials.

Here are just a few of the clinical trials:

• A double-blind, placebo-controlled safety trial using 0.3g/kg of creatine per day in men found: “creatine monohydrate supplementation is safe for health and no detrimental effects on different organs and physiological systems were observed in our cohort of volunteers.”[ref]
• In healthy older adults (aged 50-71), creatine before resistance training increased lean muscle mass and decreased fat mass. The trial ran for 32 weeks and used 0.1g/kg of creatine, compared to a placebo.[ref]
• Vegetarians have lower creatine levels, on average. A study of supplemental creatine showed vegetarians had even greater increases in bench-press strength, lean tissue, and other biomarkers than did non-vegetarians. (Both groups on creatine had better results from resistance training than the vegetarian and non-vegetarian placebo groups.[ref]
• Creatine supplementation helped both men and women increase peak power in bench presses and back squats.[ref]
• Creatine plus electrolytes increased sprint cycling times in a double-blind, randomized control study.[ref]
• Under hypoxic (low oxygen) conditions, creatine helps with cognitive function. The study included 15 healthy adults who took creatine for seven days before the 90-minute hypoxia session.[ref]

Negative study results are also interesting:

• Creatine supplementation did not significantly improve bone health in menopausal women with osteopenia.[ref]
• In fibromyalgia patients, creatine supplementation increased muscle strength, but it didn’t reduce pain or improve quality of life.[ref]

Creatine in adipose (fat) tissue:

In fat cells (adipose tissue), creatine is important in thermogenic respiration. Loss of creatine can decrease whole-body energy expenditure.[ref]

Brown or beige fat is the type of fat that creates heat in the body – especially in babies. Brown fat is darker in color than white adipose tissue (white fat) because it contains a huge number of mitochondria cranking out heat as a metabolic waste product.

Exposure to cold can trigger brown fat to produce more energy. It is essential in infants who are too young to shiver. The brown fat helps them to maintain their temperature.

In animal studies, creatine has been shown to enhance energy production when ADP is limited. When researchers limit creatine levels, the cells try to compensate by increasing the enzymes to produce more creatine. Animals lacking the creatine kinase enzyme had increased body weight and elevated fasting blood glucose.[ref][ref] The research here is new and evolving, but it looks like creatine plays a role in adaptation to cold, energy expenditure, and metabolic health.

Creatine for post-viral fatigue syndrome and Long Covid:

Post-viral fatigue syndrome is just what it sounds like – overwhelming fatigue that doesn’t end after you’ve gotten over a viral infection. It can refer to long covid or chronic fatigue syndrome (ME/CFS).

In people with post-viral fatigue syndrome (PVFS), muscle fatigue is reached much more rapidly than normal. It is thought that PVFS perturbs energy metabolism in the muscles. Research shows patients with chronic fatigue have reduced levels of hippocampal creatine also. While there is “not enough evidence to unequivocally endorse supplemental creatine for PVFS”, researchers do think it is possibly effective — as well as being low-risk and inexpensive.[ref]

In long Covid patients, an 8-week trial of creatine, creatine + glucose, or glucose alone as the placebo. showed that creatine+glucose had a large effect on decreasing body aches, headaches, and brain fog. The participants received 8 g of creatine monohydrate and 3 g of glucose per day. [ref]

Sarcopenia and creatine

Sarcopenia is the loss of muscle mass causing decreased strength in aging or chronic disease.

It is tempting to think creatine could be used to stop the aging effect on muscles, but research shows it isn’t quite that easy.

Studies in older adults show creatine supplementation alone has little effect on muscle function or mass. But… when creatine supplementation is added to weight training, the results show that it enhances the muscle’s response to training, potentially increasing capacity for higher intensity exercise and improving the muscle’s response post-exercise.[ref]

Thus, one way that creatine may be beneficial in older adults is by increasing their capacity for exercising a little longer or lifting a little more weight. Even minor increases in exercise capacity can be important in older adults, and increasing muscle mass or grip strength can help with stability and independence.[ref]

Lifehacks:

The estimated daily requirement for creatine for an adult male weighing 70kg (154 lbs) is about 2g. Most people get about half their daily creatine from their diet, with the half synthesized from arginine plus glycine.[ref]

Foods high in creatine

Animal proteins:

• One pound of beef contains around 5 grams of creatine.
• Fish is also an excellent source of creatine, with about 4.5 grams in one pound of salmon.[ref]

Here’s the breakdown from other protein sources:

When to consider creatine supplements:

1. If you aren’t eating animal-based protein-containing creatine, you may want to consider supplementing – especially if you are concerned about muscle mass or sarcopenia. Vegetarians, for example, usually have lower plasma and muscle levels of creatine.[ref]
2. Creatine is synthesized from the amino acids arginine and glycine. You may also want to consider supplemental creatine if you don’t get enough glycine and arginine in your diet.
3. You may also want to consider supplemental creatine if you have any genetic variants related to lower creatine creation.

Let’s dig into the research on creatine supplements – how much, how often, and how is it absorbed:

Safety and Dosing of Creatine Monohydrate:

Creatine monohydrate comes as a flavorless powder and easily mixes into water or a drink, or you can get it in flavored drink mixes.

What does supplemental creatine do?

There is quite a bit of research showing supplemental creatine is beneficial in exercise and in strength training. It isn’t a miracle supplement that will make you look like Arnold Swartzenegar, but hundreds of research studies show it gives a bit of a muscle-building and muscle-repair boost.

You may have read that creatine supplements can cause weight gain. Researchers think the initial weight gain sometimes noticed with higher doses comes from increased water weight and not from increased body fat.[ref]

Safety and quality:

As with all supplements, choose a high-quality brand to avoid contaminants. Labdoor is one company independently testing the purity of different creatine brands. ConsumerLab.com is another company that does independent testing of supplements and reports on their quality and cost. All of the supplement brands that they tested contained creatine within the range of the amount listed on their labels. They also tested to make sure that the supplemental creatine didn’t contain an unacceptable amount of creatinine or dicyadiamide. On ConsumerLab.com, brands that passed their testing included BulkSupplements (top pick), GNC, Legion, Optimum Nutrition, PEScience, Thorne, Universal Creatine Chews (top pick), and Old School Vintage Build.[ref]

Dosing:

Studies often use a large loading dose of 20g/day for 5-7 days, followed by chronic dosing of 3-5g/day with no safety issues.

Safety assessment studies show creatine is safe at doses of up to 5g/day for long-term supplementation in healthy adults.[ref]

If you have health concerns, especially kidney disease, you should talk with your doctor to be sure that creatine is safe for you. The studies on healthy people show creatine to be safe, but there are a few case studies with chronic kidney disease patients having problems with supplemental creatine.[ref]

Side effects and cautions with creatine supplement:

Anecdotal reports on the web mention gastrointestinal distress when using higher doses too quickly. If you aren’t using creatine for bodybuilding and find it gives you intestinal issues, try going with the lower doses to start with.

If you have asthma, talk with your doctor before supplementing with creatine.  Studies in mice show that creatine may exacerbate airway sensitivity which theoretically could make asthma worse.[ref]

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