Creatine (Cr) is a naturally occurring substance in the body (made from the amino acids arginine, glycine and methionine) and it is found primarily (95%) in muscle cells and the brain. It is also an effective supplement for overall health and well-being. It has great impact on both athletic performance and health. It helps improves exercise performance and accelerate muscle growth, it assists in bone health maintenance, and improves how the brain functions. All while helping to stave off, or treat, many neurological diseases. It also reduces fatigue, and is showing promise as an alternative treatment for depression, especially the drug resistant variety. It is also being examined as an alternative treatment for post traumatic stress disorder, and other anxiety disorders.
Creatine helps support physical performance. Creatine (Cr) supplements increase your muscles’ phosphocreatine stores (1;2). Phosphocreatine helps with the formation of something called Adenosine triphosphate or ATP. ATP is a key molecule in cellular energy production, as well as all basic functions of life (2). In fact, it is the most basic form of energy in your body’s cells. ATP plays an essential part in metabolism and muscle function. Unfortunately, during high intensity physical or emotional exertion the body can only store enough ATP for eight to ten seconds of high-intensity effort. After which, the body must manufacture enough new ATP sufficient to meet the needs of the activity (3).
Though creatine is most often thought of as a male body building supplement, studies have shown that it does benefits women regarding increased strength and overall toning. One study on women supplementing with creating found that those women taking creatine experienced a 60% higher increase in lean muscle mass when compared to a group of women not taking it, but following the same exercise and diet protocol (4). Further, an analysis of more than 150 studies on the effects of creating on women’s physical health regarding weight/cardio training showed that the average women taking it experienced an average increase of 2.2% in lean body mass, while at the same time experiencing an average reduction of 3.2% of body fat (5).
Creatine (Cr) can radically improve high-intensity exercise performance (11;12; 13), it magnifies many aspects of physical activity, including the following (14;15;16;17;18;19): ballistic power, cognitive performance/brain health, muscle mass and endurance, resistance to fatigue, recovery, strength, and sprint ability. What makes creatine great is its ability to help even the most novice of athletes improves their performance (9 ;10).
During exercise a bodily substance called adenosine triphosphate (ATP) is broken down to produce energy. As the rate of ATP re-synthesis limits the body’s ability to continually perform at maximum intensity, the body uses ATP faster than it can reproduce it (6;7). Creatine (Cr) supplements increase phosphocreatine stores, allowing for the better or greater production of ATP or energy to fuel muscles during high-intensity workouts or exercise (7;8). This is the primary mechanism behind creatine’s performance-enhancing effects. In fact, creatine improves high intensity activity by as much as 15% (9; 10). In short, creatine supplements provide supplementary energy, this in turn improves high-intensity exercise or physical performance. This effect is due to the part it plays in producing called adenosine triphosphate (ATP).
Creatine helps build muscle and is known to enhance the muscle building process (11;4). This is due to its ability to alter or change a number of cellular pathways which lead to new muscle development or growth. For example, creatine improves protein formation in new muscle fibers (12;56; 57;53;54). And, creatine can increase something called insulin like growth factor 1 (IGF-1), also called somatomedin C. This is a hormone similar in molecular structure to insulin. It has an anabolic effect in adults, meaning it plays a significant part in building molecules from smaller units. IGF-1 is important in the building up process of metabolism, in this case leading to the body’s ability to build and maintain muscle. So, creatine’s effect also promotes an improvement in muscle mass (12;56). What’s more, creatine supplements can increase the water content of your muscles, called cell volumization. This process can quickly increase muscle size (53;55). Furthermore, some studies show that creatine reduces levels of myostatin, a molecule which stunts muscle growth. So, lowering myostatin can accelerate muscle gain (21). In short, creatine stimulates many biological functions leading to increased muscle size and growth.
Regarding muscle mass, which deteriorates with age,creatine is considered by some to be the world’s most effective supplement for increasing this muscle and combating age related muscle loss (11;20). Studies have shown that simply supplementing with creatine for five to seven days can markedly improve or increase both muscle size and lean body weight. Keep in mind that these preliminary improvements are the result of an upsurge in water within muscle tissue (11;55). In the longer term, creating assists with muscle fibre growth. It does this by signaling key biological pathways, while also improving strength-based muscle performance (12;56; 57; 53;18).
A wide-ranging review of scientific literature showed a consistent result in studies of creatine (Cr) and muscle gain in which those subjects taking Cr gained more muscle than those in control groups, who did the same exercise, but did not take supplements (20). For instance, a study involving participants following a training regiment for six weeks while taking creatine added an extra 2 kilograms (4.4 pounds) in muscle beyond the muscle mass developed by the control group (18). This wide-ranging review went so far as to look at how well Cr effected performance when compared to other, more popular, sports supplements, and it was found that creatine was the better choice. Creatine is considered to be safer than many sports supplements. Another benefit of creatine is its relatively inexpensive cost (20).
Creatine may assist with hypothyroid related muscle wasting. Thyroid disorders are associated with increased muscle loss and muscular disorders. When the body is trying to build more muscle, it releases creatine kinase into the blood stream. After creatine (Cr) is naturally produced by the body in the liver and kidneys it enters the bloodstream and is moved to where it is needed. About 5% goes to the brain, the rest to the muscles, which have high energy demands. The presence of Cr in muscles is associated with exercise related damage. When creatine acts as a type of enzyme, called a kinase, it modifies another molecule, which accelerates ATP production, allowing for quicker healing. A study found that there is a strong correlation between low levels of thyroid hormone T3 in the blood and higher than normal levels of creatine kinase (22). This is why hypothyroidism is associated with, and sometimes tested by measuring, the amount of creatine kinase in the blood. The thyroid gland regulates the metabolism (heart rate, blood flow, rate at which food is metabolised, fat burning), and it is this metabolic activity of which creatine is a part. This fact may be why muscular disorders are associated with thyroid problems. At the moment the association is known, but the cause is not.
If you have a thyroid problem, make sure to let your healthcare provider know if you are taking creating supplements before undergoing any thyroid testing.
Creatine can also reduce fatigue and tiredness (23). This is because it can improve energy production within cells while also increasing dopamine levels. Dopamine is both a neurotransmitter and a hormone, depending on where it is found in the body. It is used in the brain to send signals from one cell to another. It is associated with motivation as well as motor control and the release of numerous hormones. Regarding creatine’s role in fatigue reduction, one study of fatigue, testing the use of creatine by athletes taking a cycling test in high heat, found that it did reduce fatigue (58;59). Regarding fatigue and the effects of creatine, a study looking at how creatine impacted dizziness on those suffering from traumatic brain injury, found that while 80% of the control group reported fatigue, only 10% of the test (creatine) group did (23). Regarding dizziness, creatine supplements reduced this by 50% (23). A study on sleep deprivation noted that creatine supplements reduced fatigue while increasing energy levels (24). Creatine helps guard against heat related fatigue during exercise as well as lowering the amount of sweat produced and helping the body to better regulate temperature (60). In one study of male athletes, 21 endurance trained volunteer who were not used to training in high heat and who had not taken creatine for 8 weeks prior to the study, were broken into two groups. Before being given creatine or a placebo/sham the athletes trained for seven days to exhaustion (constant load exercise). They were then broken into two groups. The creatine/test group received 5 grams of creating four times a day, plus 35 grams of carbohydrates, for seven days. The other/control group received 40 grams of carbohydrates four times per day or 160 grams in total, for seven days, the time needed to move the creatine into the muscles. After taking the creatine long enough to get into the muscles the tests were performed again. The findings: the creatine/test groups’ time to exhaustion became significantly longer, and their body mass increased, they also experienced a significant change(lowering) in the body temperature of the creatine/test group as well as a significant decrease in the rate of sweat they produces. The finding was that creatine induced an improvement in the water content of the body, called hyperhydration, which resulted in a more efficient thermoregulatory response. This is the body’s ability to maintain a consistent temperature or to regulate its temperature, even when it is different from the environment, and example is sweating in heat.
Creatine has anti-inflammatory properties: it tempers inflammation caused by free radicals, at least exercise related inflammation. The results of a study (90) of creatine’s effect on muscle soreness and inflammation “indicate that creatine supplementation reduced cell damage and inflammation after an exhaustive, intense race.” The study used experienced runners performing in a 30-kilometer race. The subjects were broken into two groups, a test/creatine group and a parallel/control group. The first group was given 20 gram of creatine and 15 grams of maltodextrine per day for five days prior to the race, and the control/parallel group was given only the maltodexrine for five days prior to the race. The researchers looked for signs of inflammation and soreness in the muscles (blood was taken looking for: creatine kinase, lactate dehydrogenase, prostaglandin E2, tumor necrosis factor-alpha) in all participants both before and after the 30 Km race. Blood samples were re-taken directly after the race, and at the 24-hour post race mark. The results showed the following: the treatment /creatine group had only a 19% increase in creatine kinase for the treatment/creatine group, vs a 400% increase in creatine kinase for controls; no change in lactate dehydrogenase plasma concentration for treatment/creatine vs. a 43% increase in lactate dehydrogenase in the control group; a 61% increase in prostaglandin E2 for treatment/creatine group vs. a 600% increase in prostaglandin E2 for controls; and a tumor necrosis factor-alpha increase of 34% for treatment/creatine vs. a 200% increase in tumor necrosis factor-alpha for the controls. And, no one in the treatment group reported any side effects.
Preliminary studies (using animals) demonstrated that creatine (either taken by mouth or injected) decreased the inflammatory response in several different models of acute inflammation. This is proving to be true in studies of chronic inflammation as well. Arthritis for instance has been shown to benefit from creatine treatment in animal models/studies (92). And, studies with people are also indicating that these effects help treat post-exertion/exercise related muscle-based inflammation. Creatine has been shown, in two different animal studies, to have favorable effects on the progression of arthritis. Most importantly, regarding inflammation, human trials have shown these effects to translate to exercise; studies have demonstrated that creatine reduced markers of inflammation following an Iron Man style triathlon (90), a thirty-kilometer food race (93), and an aerobic (running) test (94).
Creatine may protect against oxidative stress. Regarding oxidative stress specifically, studies (cell cultures in the lab) have shown that creatine has the ability to protect cells from oxidation related harm (92). An animal study (28 days of exercise and with a control group) showed that creatine supplementation “creatine supplementation inhibits increased oxidative stress markers in plasma and muscle induced by acute exercise (95, p.1)”.
Creatine can positively impact the immune system: it has, in the lab, tempered the immune response in (vascular) endothelial cells (96). Creatine has a protective effect, in the lab, vis-à-vis atherosclerotic plaque. The researchers stated that “we examined the effect of CR supplementation on endothelial cell parameters in vitro, and found that it inhibited endothelial permeability, neutrophil adhesion to endothelial cells, and adhesion molecule expression. It is suggested that CR supplementation may serve as a suppressor of inflammation at the endothelial cell level (96.p 178-179)”.
Creatine may have protective effects regarding heart disease and can enhance recovery after a heart attack. Supplementing with creatine lowers triglyceride (fat in blood) levels, which may help protect against heart disease. Creatine supplements have been reported as lowering homocysteine levels. Homocysteine is related to heat disease, like heart attack and stroke (105). Homocysteine is a type of amino acid. Of a person has too much of it they may develop hyperhomocysteinemia. This condition contributes to blood clots and arterial damage in blood vessels. This condition is usually the result of a B 12 deficiency, as B vitamins help convert it into cysteine.
In some studies of heart failure patients, those individuals taking creatine as an adjunct to standard medication increased their exercise output before reaching fatigue when compared to a control group. In one study of the effects of short-term creatine supplementation, using 20 heart failure patients, found that the addition of the supplement to regular medication improved muscle strength while increasing body weight.
Creatine has, according to preliminary studies, the ability to improve bone development/maintenance in older adults, especially post-menopausal women. Currently, creatine and its ability to improve cellular energy is being investigated for its beneficial effects on the brain, aging, and even bones (63; 77). Bone health in particular is a primary concern to post menopausal women, as this population is especially vulnerable to weakening bones. This situation can lead to fractures, frailty, and a loss of function on a daily basis (64).
Exercise improves bone density and so is good for both bone strength and tissue health. Small studies of creatine (Cr) are showing it to have the ability to enhance bone mineral density. Bone mineral density is the amount of bone mineral in bone tissue. The more minerals present in the bone, the greater its strength, and the less likely it will be to degenerate or brake/fracture.
Creatine (Cr) supplementation may improve bone health in a multiplicity of ways. Firstly, Cr is used by the bone cells for cellular energy stimulation (7). So, by increasing creatine within the body as a whole, the bones have a better or enhanced access to creatine. The more creatine, the more metabolic activity within the bone cells. this means there is a greater chance that new bone is formed and that more minerals are absorbed, leading to greater bone strength and health (8). Secondly, Cr improves muscle performance (3; 4;5). The stronger the muscle, the more the muscle stimulates the bone, the greater the stimulation the more likely it is that the bone mass density will improve or increase (6). in order to garner the greatest effects from taking creatine for bones, resistance/weight training should be undertaken three times per week (67;71).
Creatine should be combined with weight/load bearing exercise to result in improved bone health. A small placebo-controlled study (9) which also controlled for diet (via food journals) of postmenopausal women (half of whom took creatine for one year) showed that weight training (three times per week) combined with creatine supplements (seven grams) results in: the maintenance of bone mineral density; a mild increase in bone strength; and a mild increase in muscle strength. Conversely, the placebo/sugar pill group lost a significant amount of bone mineral density. The bone tested was the Femur, which is a large leg bone, and often prone to fracturing with age (1;10).
Some research is showing that for older adults it is better to take creatine right before, or during, exercise (11). It is hypothesised that creatine taken at this time increases the blood flowing to the muscles under exertion during exercise. This then results in better, or more, creatine being transported/moved into the muscles and building up or accumulating into the muscles (11). The best option might be to take it just before exercise. This was shown in two studies to increase muscle uptake of creatine as well as muscle concentration of creatine. Both of these factors can lead to better overall results regarding muscle health and performance (12;13). When choosing a dose of creatine, effective dosing (after the first week of taking the full scoop to get it into the muscle) is approximately three grams or half a tea spoon. In short, creatine in combination with exercise and other dietary proteins is important regarding bone and muscle health during the aging process, especially for postmenopausal women (14).
Creatine supports skin health and protects against, and reverses, age related skin damage. Or, that which is associate with aging is connected to damage to skin cells, especially within the mitochondria and DNA. Mitochondria, found in every cell, converts nutrients from food into energy. Aging is related to dysfunctional mitochondria (102). So, creatine is important in preserving the skin’s (and body’s) cellular energy system. It is turned to phosphocreatine (its phosphorylated form) in the body and, in this way, acts as a pivotal source for high energy phosphates, one of three components of ATP or adenosine triphosphate. The other two are sugar or ribose, and a nitrogen base called adenine. As aging sets in, and oxidative stress does more damage to cells, it becomes more difficult for the body to maintain the creatine system, and so more difficult to maintain the concordant energy storage mechanism in skin, in this way skin is negatively affected by a loss of creatine. The aging of the skin specifically is associated with a deterioration in cellular energy metabolism. This loss of energy is the result of harmful changes in mitochondrial function. This in turn is the result of free radicals created by solar ultraviolet (UV) radiation, called exogenous noxes (103). In short, as skin ages the cells try to counter any loss of mitochondrial energetic capacity by producing extra-mitochondrial pathways like glycolysis or the creatine kinase (CK) system.
A study of creatine metabolism and skin aging showed that aging is associated with a stress related deterioration in the mitochondrial energy supply in human skin (epidermal) cells, which is associated with a reduction in mitochondrial creatine kinase (Ck) activity (103). The same study shows that creatine supplementation is taken up by skin cells, where it is correlated with an increase in mitochondrial CK activity, improved mitochondrial functioning, and provided protection from free oxygen radical stress, or free radicals/oxidative stress (103).
The study showed that creatine supplements were taken up by the outermost layer of the skin’s cells, called keratinocytes. These make up 90% of the outermost layer of skin, the epidermis. Keratinocytes are also found in the deepest layer of skin, called the basal or stratum basale layer. These special cells help wounds heal by migrating to fill the gap created by the wound. They can help form new hair follicles in areas where these have been damaged and need to be regenerated. Damage to Keratinocyte cells are associated with sun damage (UVC/UVB/UVA), and aging cells which no longer reproduce themselves properly, and often spontaneously cellular death. The study showed that taking creatine markedly protected against a variety of cellular stress conditions, like oxidative and UV damage (103). When creatine is combined with CoQ10, both have antioxidant like properties, these two supplements may have a synergistic effect, improving both (104).
Creatine can assist with brain/cognitive functioning (9). The brain needs significant amount of Adenosine triphosphate (ATP) and research demonstrates that the brain requires a substantial quantity of ATP when engaged with difficult cognitive, or thought related, tasks (9). Creatine supplements can improve the amount of phosphocreatine in the brain. Phosphocreatine or creatine phosphate (CP) is type of creatine molecule that rapidly mobilizes reserves of high energy phosphates in both muscles and the brain, and which can recycle ATP, the main provider of energy at the cellular level. Basically, creatine supplements help with ATP production in the brain. Creatine can also assist with cognitive functioning by improving both mitochondria functioning and dopamine levels (9;25;26). The first, mitochondria, mainly perform cellular respiration, meaning it takes nutrients from the cell, breaks them down, and turns them into energy. The second, dopamine, is a hormone in the body and a neurotransmitter in the brain. As a neurotransmitter it plays a pivotal role in motivation. Creatine is especially helpful with cognition in times of stress (sleep decrepitation, exercise, and stressful cognitive activities like math). Vegans and vegetarians, who tend to lack protein in the diet, may also be assisted by this.
Regarding age related cognitive decline and creatine, research is showing that after two weeks of supplementing older adults show a substantial improvement on both recall ability and memory (49). And, in these subjects specifically creatine supplements could assist with the following: boost brain function; protect against neurological disorders; and diminish age-related muscle loss and concordant loose of strength (50). Keep in mind that creatine from food sources take a lot longer to digest than those from supplements.
Creatine can be an adjunct, or additional, treatment for neurological disorders. Creatine might have protective qualities concerning neurological disorders. Research (primarily animal) implies that creatine can, when combined with medical treatment, help treat the symptoms of neurological diseases, as well as their progression, and even positively impact the life expectancy of those suffering from neurological diseases. This is because several neurological disorders have the same factor in common, a reduction in brain phosphocreatine (27). They also involve an overabundance in stress related reactive oxygen species or free radicals (28). Creatine supplements can increase levels of phosphocreatine, so it can help avoid, or at least slow down the development of, neurological problems. Creatine also helps address free radicals.
Dementia: Creatine helps cells work efficiently, so they don’t have to work as hard, the aging process is slowed and the cells survive longer before dying off. Individuals diagnosed with dementia (Alzheimer’s or Parkinson’s) as well as other conditions have exhibited improvements to brain health after taking creating. It helps to reduce the dosage of other medications and lowers the number of side effects, and helps improve oxygen in the brain. The last improves mental functioning and lowers mental fatigue. It also improves outlook/mood. Creatine can help improve cognitive functioning, even when the person lacks sleep.
Alzheimer’s dementia: may be reduced through the taking of creatine (50). Creatine has, in animal studies, proven to protect brain cells from damage related to beta amyloid plaque toxicity. Alzheimer’s disease is believed to be caused by a build up of beta-amyloid plaques and tangles in a substance called tau. Both are produced within brain cells, reducing or eliminating the cells ability to function properly. Research is showing that those individuals who develop Alzheimer’s have lower levels of phosphocreatine when they enter into the first stages of the disease (50). They experience up to an 86% reduction in the activity of an enzyme (creatine kinase) that stimulates creatine to make energy in cells. They can also experience up to an 14% reduction of in creatine kinase protein expression (50). At its worst, Alzheimer’s symptoms involve confusion, deteriorating cognitive functioning, a loss of long-term memory, and sever dementia. It is now thought that creatine supplementation may assist in protecting against Alzheimer’s, as creatine within cells makes energy.
Creatine may help protect against or even help improve symptoms of dementia. This is because it improves the way cells thought out the body work. All cells have mitochondria, this is where food etc., is made into energy. It becomes dysfunctional before the onset of dementia. It is this dysfunction that may be the root of dementia (109). Cells slowly stop working properly because when energy in the cells is made, by products can also be produced. When energy is created a by-product is also made. It is called lipofuscin or aging pigment. Ideally, it is washed out of the cell. But, with age, it starts to build up and contribute to dementia and its symptoms (problems with memory, lack of decisiveness, Parkinson’s, Alzheimer’s, and dementia). Creatine slows cellular damage from excitotoxicity, specifically damage from a toxic substance called Abeta proteins. It can protect cells from Abeta related damage (87;110). This toxin is specific to Alzheimer’s disease (111).
Creatine also assists in the removal of an age-related substance called lipofuscin. Lipofuscin is a yellow-brown substance that is associated with age-related disruptions to cells ability to remove toxins that can cause damage. Toxins speed up oxidative stress and damage to cells. They also slow the cells’ ability to produce energy. Toxins and the disruptions they cause can result in the effected cells dying prematurely (79;80). In animal research, creatine has been shown to reduce the presence of lipofuscin (82). This allowed for the animals to live up to 9% longer in comparison to animals with the same physical condition but not given creatine. The nine percent in mice when converted into human years is approximately seven years for a human. It should also be noted that the animals given creatine also performed better on tests of neurobehavior (82;113).
Parkinson’s disease may be treated partially with creatine. This condition is characterized by a decrease in dopamine, which is a key neurotransmitter for brain health (2;29). An excessive drop in dopamine production within the brain can lead to brain cell death, as well as many symptoms of Parkinson’s disease including the following: loss of muscle function, tremors, and speech impairments (29). Research (using animals) on creatine and Parkinson’s disease, has shown that creatine supplements can prevent up to 90% of the comorbid loss in dopamine (27). Concerning other Parkinson’s symptoms, sufferers often try to maintain muscle mass to improve strength and functioning, so they weight train. Creatine is a great assistant in building muscle (30;31). One study those Parkinson’s patients who took creatine and did regular load-bearing exercise improve more on measures of strength and daily functioning when comparison to Parkinson’s patients who only did load-bearing exercise (32). Keep in mind that it may be necessary for Parkinson’s patients to take more creatine than healthy individuals. Some studies of Parkinson’s patients and creatine have shown that patients taking between four and ten grams per day, the recommended amount for healthy people, don’t show a significant improvement on measures of daily activity (33).
Huntington’s disease can benefit from creatine. In a (animal) study of creatine supplements and Huntington’s, supplements restored brain phosphocreatine levels to 72% of the subjects’ pre-disease levels, in comparison to only a 26% improvement in the no creatine control subjects (34). Further, this renewal of phosphocreatine facilitated the preservation of daily functioning. It also lowered cell death by about 25% (34).
Creatine supplements may assist with treating other neurological problems (35; 36;37; 38). Keep in mind that much of the research has been done on animal subjects. These diseases include: Alzheimer’s, Brain injury, spinal cord injury, Epilepsy, and ischemic stroke. Creatine is also showing promise regarding Amyotrophic Lateral Sclerosis (ALS), or Lou Gehrig’s disease. ALS is an ailment that affects motor neurons, which are necessary for movement. In this case the brain loses the ability to communicate with muscles. The body loses the ability to move at will. Eventually, the muscles break down, and the ability to walk, talk, eat, swallow, and breathe is lost. In one study creatine improved motor functioning, while reducing muscle loss. It also prolonged the survival rate of patients by about 17.5% (39).
Stroke damage may be improved by creatine: stroke is often the result of a lack of sufficient blood supply to the brain, or some of its parts. Stroke most often occur as a result of insufficient blood supply to areas of the brain. Decreased blood flow to the brain is associated with excessive amount of a substance called lipofuscin within the brain (78). Lipofuscin build up is the end result of a disruption of the cells ability to remove dysfunctional components. This ability is called autophagy. As autophagy slows down, and lipofuscin builds up, there is an upswing in oxidative stress, and a concurrent decrease in energy, leading to cell death (79;80 81). Animal studies are showing that creatine has the ability to boost cellular energy and to reduce built up lipofuscin within the brains of the subjects (82; 83). Creatine also assists with the preservation of necessary levels of high-energy phosphate-based molecules within tissues (brain, heart, muscle) needed in times of high energy usage (84;85; 86). Further, creatine enhances the production of ATP, an energy transfer molecule, which helps full cellular metabolism High levels of creatine support the body’s production of ATP, the universal energy-transfer molecule, when ATP itself is used up by these power-hungry tissues (87;88). Some research suggests that cellular level brain damage due to stroke is associated with higher levels of Lipofuscin. So, creatine, with its capacity for depressing lipofuscin, can be of some benefit with this aspect of stroke. Animal studies of creatine administration after stroke (reduction in blood flow) have shown a significant reduction in brain damage regarding the size of the area damaged (89). In addition, creatine supplementation also replenished stroke depleted ATP. Even though there were no human studies of creatine’s impact on stroke related brain damage available when the animal research was carried out, the researchers still suggested that, given creatine’s safety record, those at high risk of strokes consider creatine supplements (89).
Diabetes may be either staved off or treated with creatine, which can help lower blood sugar levels. Creatine increases the functioning of a transporter molecule (called GLUT4) that moves blood sugar into muscle tissue (40;41;42;43). This was shown in a study of creatine’s ability to improve changing blood sugar levels after a high carbohydrate meal. This study had people combined exercise with creatine supplements, and others (control group) only exercise. Those subjects who took creatine had greater control over blood sugar levels than subjects who only exercised (42). This study’s result should not be overlooked as short-term post-meal changes in blood sugar levels are important indicators of diabetes risk. The sooner sugar is removed from blood, the better off the person is (44). Keep in mind that the research mentioned is preliminary, more research in general, as well as long-term studies, on creatine’s effects on blood sugar need to be done. Keep in mind that Cr supplements are not advised if you are in danger of developing kidney disease.
Depression may be improved by creatine supplements. Preliminary studies are showing it to have protective effects against, as well as an ability to treat, the symptoms of depression. This might be due to the fact that it increases Adenosine triphosphate or ATP. In short, creatine speeds up cellular metabolism within brain cells. Studies show that after taking creatine the brain is better able to use primary brain fuel oxygen (45), so it functions better. This is important as there is a growing body of scientific evidence that depressed people’s brain does not metabolize energy the same way a non-depressed person does (28). Studies using functional brain imagine (positron and single photon emission tomography or PET scans) have shown that the brains of depressed people often have diminished blood flow and metabolism. Specifically, in the frontal lobes and the basal ganglia. In one study of depression and creatine, which used measures of creatine in spinal flued, it was found that those subjects who were depressed, and expressed a desire to commit suicide, also had lower levels of creatine in their spinal fluid (28).
How creating works (28): Once creatine passes the blood brain barrier, it is taken up from extracellular fluid by neurons and oligodendrocytes by CRTs, where it serves its primary role as an energy shuttle and regulator of energy homeostasis. Recent work mapping the regional and cellular locations of CRTs found the highest level of expression in neurons within the olfactory bulb, hippocampus (granulate cells of dentate gyrus), cerebral cortex (pyramidal neurons), cerebellum (Purkinje cells), brain stem (motor and sensory cranial nerves), and the spinal cord (dorsal and ventral horns), whereas the lowest levels of CRT expression was found in the basal ganglia and white matter. It is important to note that many of the brain regions that express CRTs are compromised in conditions like Alzheimer’s Disease, Huntington’s Disease, and psychiatric disorders, to name a few. Loss of CRT-containing tissue may further contribute to cognitive or emotional deficits observed in numerous brain-related disorders.
Constant replenishment of creatine from either the diet or biosynthesis is necessary. Once inside a cell, creatine is phosphorylated for energy storage, a process to be described in more detail below. This reversible conversion results in a spontaneous non-enzymatic by-product called creatinine, which is excreted from the body by the kidneys. High energy demands required by numerous cellular processes also deplete stores of phosphorylated creatine. The rate of depletion of creatine resources is estimated at approximately 1.7% of the total pool per day. Since the majority of creatine is found in skeletal muscle, the rate of reduction varies across gender and age.
Several research studies, using both animal and human subjects, have shown creatine to be a prophylactic against depressed mood (28). One (double blind, meaning no on new what was being given to whom) human trial, using female subjects who were not responding to medication (called treatment resistant) found that those women taking 5 grams of creatine supplements in combination with selective serotonin reuptake inhibitors (SSRIs), a common type of antidepressant, showed greater improvement on the Hamilton Depression Rating Scale (Ham-D) than the subjects assigned to a placebo or sugar pill. Interestingly, the creatine group showed improvement in only two weeks (61). In a four-week study that compared how depressed people reacted to 3 to 5 grams of creatine versus how bipolar individuals reacted to it, the study found that those who were depressed benefited from the supplements, but those who were bipolar became mildly manic (45). Interestingly, it has been found that high baseline levels of phosphocreatine in a depressed person can predict how well they respond to SSRI’s/medication for depression when it is mixed with thyroid medication triiodothyronine (28).
Regarding anxiety, in a study of people suffering from generalized anxiety disorder or GAD, but no childhood trauma, it was found to have reduced levels of total creatine in the cerebral white matter or brain tissue (28). A similar level of low creatine was found in a study of people who experienced panic attacks, but this time in the right amygdalohippocampal region of the brain. And, another study of panic disorder found creatine levels to be asymmetrical, with more phosphocreatine in the right frontal lobe than the left (28). In an animal study, using both male and female rats, those rats on creatine, regardless of sex, exhibited less anxiety than animals not given it (46).
Creatine is proving to be an adjunct or alternative treatment PTSD: it is now being investigated as a potential treatment for post traumatic stress disorder or PTSD combined with depression. Further, in studies of PTSD, using a control group, it was found that subjects diagnosed with PTSD had reductions of creatine in both the right and left hippocampal brain regions. Preliminary studies on creatine for PTSD are showing some success. A study of PTSD, where subjects were treatment resistant (drug resistant), found supplements improved symptoms in both men and women. The greatest response was in those subjects who had PTSD and depression. So, there is some proof that creatine can be therapeutic for PTSD. Regarding anxiety disorders specifically, there are few studies at this point. One case study, on a 52-year-old female who suffered from depression, fibromyalgia, and PTSD, found that the subject had abnormally low levels of phosphocreatine and ATP. She was unresponsive to medications before creatine supplements were introduced. After daily supplementation of creatine there was a reported improvement on measures of depression and fibromyalgia, and a 30% improvement on an overall quality of life scale (28).
When it comes to creatine doses for phycological problems, it is suggested that using lower doses (5 g) of creatine may be better and have more bioavailability, in comparison to higher (10 g) doses. This is as larger doses may slow the absorption of creatine. Smaller doses usually absorb in about two hours. And larger doses can cause the saturation of target sites in the body, resulting in a downregulation of, or lowering of priority of, creating in the cells. Tissues that are lower in creatine before supplementation show greater accumulation of it after supplementation. Keep in mind that it takes about four weeks for creatine supplements to build up in the brain and muscle tissue (28). An example is an experiment in which people given 5 g of creatine a day for four weeks found that the subjects experienced a significant increase in total brain creatine. This was especially true of the following brain areas: thalamus, cerebellum, white matter, and gray matter (28).
Creatine supports gut health. Creating has an important part in maintaining a healthy gut barrier. A healthy gut barrier stops the contents of the gut from leaking into the blood stream and causing inflammation, amongst other things. So, in this way it prevents leaky gut. This is important as if unchecked, leaky gut leads to inflammatory bowel disease (IBS). A dysregulated gut barrier is a major indication of IBS. So, creatine can reduce the severity of intestinal disease.
Clinical trials are showing that creatine benefits gut health. It is now being studied for its effects on IBS related mucosal inflammation. It has a significant role in the metabolism of intestinal epithelial cell energy as it increases ATP production in all cells. So, it impacts digestive tract tissues. it is necessary for the maintenance of gut barrier functioning (this allows the digestive tracts to let nutrients in and keep unhealthy particles out). Creatine supports the production of enzymes, normal digestion, and gut homeostatic, meaning balance or self-regulation (106;107). In a case study of a 33-year-old male suffering from Chron’s disease like gastro-intestinal symptoms (anal pain, hematochezia, secondary and non-healing anal fissures, rectal bleeding, cramping abdominal pain and loose stools). The man had been taking 1 gram of creatine a day. This was stopped and he was put on anti-inflammatory medication (mesalamine). He got worse, not better. A colonoscopy showed more extensive ulceration and worsening ileitis after time on the medication. The patient then requested a trial of creatine, as it had been previously helpful. The mesalamine was stopped and a regiment of 1,034 grams of creatine per day was started. the patient reported significant improvement in his symptoms. Another colonoscopy, 6 months after creatine was started, showed that the previous extensive ulceration and inflammation was significantly improved and only one, small, ulcer was found (108).
Creatine for intestinal health, IBS, and colitis. Creatine replenishes ATP. It is maintained by diet and endogenous synthesis, meaning it is made from other nutrients in the body. Creatine helps maintain intestinal homeostasis or balance. This seems to be lacking in people with intestinal problems. When inflammation occurs in the intestines, The epithelium or inner walls of the intestine exhibit increased hypoxic stress. So, it needs more energy to try and maintain this barrier. Creatine can provide the energy needed in the face of an acute illness when increased energy required. It also facilitate the transfer of high-energy phosphate in the cell’s mitochondria. This is helpful during the regeneration portion of the mucosal barrier production. If this barrier is not properly repaired, the person is more likely to develop colitis or other intestinal problems (106).
Creatine can improve sex drive in both men and women. Creatine has been shown in some studies to improve active testosterone called DHT or dihydrotestosterone. Both men and women have testosterone and DHT circulating in their bodies, though women usually have far less of both. DHT is associated with sex drive in both sexes, so by improving DHT production, creatine supplements also enhance libido. DHT, and so creatine, is also known to improve self confidence.
A test of creatine’s effects on dihydrotestosterone (DHT) in young, male, athletes found that after seven days of creatine loading, followed by 14 days of maintenance (lower dose) the subjects had no changes to their serum testosterone levels, meaning that the testosterone itself did not rise. But the subjects had an average increase of 56% in their DHT after the initial seven days, and it remained at 40% on the maintenance does. Further, the ratio of DHT to testosterone increased by 36% after the initial seven days. It remained elevated by 22% on the maintenance does. It is hypothesized that the creatine effected the enzyme which converts free testosterone to DHT, called 5-alpha-reductase. Keep in mind this was the only study to test for DHT or testosterone surges due to creatine. This was a study of male testosterone and DHT levels (62 1006). While women also have DHT, which can improve sex drive and self confidence when balanced, DHT does not female impact hair loss the same way it does male hair loss.
Regarding hair loss specifically, there is no consistent clinical data indicating that creatine will cause this in either men or women. And, regarding women, overly high DHT levels play less of a role in hair loss than it does in men. Women who experience hair loss usually have a genetic predisposition to this condition. Estrogen levels also play a great part in female hair loss (48 1011).
If you are concerned about your dihydrotestosterone (DHT) or testosterone levels, get them tested. Treatments for high DHT include lowering prescription testosterone (if you are taking it), and the prescription medication Finesteride.
Natural treatments for high DHT include: Beta-sitosterols, Gamma Linolenic acid (GLA), green tea, Lipsterolic extract from Serenoa repens, pumpkin seed oil, Pygeum africannum, saw palmetto, and a combination of 5% hexane extract of C. aeruginosa and 5% minoxidil. This slows hair loss and increases hair growth (47).
Sources of creatine include both food and supplements. Regarding food, meat is the best dietary source, so vegetarians are often low on it. For instance, one study on vegetarians found that those who took creatine supplements had a 20–50% improvement in measures of intelligence and memory (9).
Creatine may interact with large amounts of caffeine (like that found in body building supplements) in a negative way (98). A few studies have indicated that if large amounts of caffeine are mixed with creatine, there can be a negative side effect. Caffeine and creatine may have opposing effects on the amount of time muscle needs to relax, basically the supplements are counteracting one another. Another suggestion for this negative interaction is that creatine mixed with caffeine results in gastrointestinal distress. Caffeine is an aid for endurance exercise, but it may not be helpful for short bouts of exercise or for load-bearing/or weight training exercise.
Creatine supplements are one of the most researched supplements, with the oldest research going back over 200 years. Many studies show that it is safe for long-term consumption. There have been long-term (five year) trials where no negative effects were reported by healthy subjects (11). Supplementing is simple. Take between three and five gramps (.70 to 1 tea spoon) per day of creatine monohydrate powder (11; 51). There is conflicting information as to when creatine should be taken. In studies of depression, it is recommended that it be taken first thing in the morning with plenty of water. Studies on the effect of creatine on muscle mass have tested it before, during, and after, weight training. All tests showed positive results.
Rarely reported side effects include the following: weigh gain, weight loss, gastrointestinal distress, loose stools, altered insulin production, the body slowing production of the creatine it makes, (inhibition of endogenous creatine synthesis) which goes away when supplementing stops, renal dysfunction, and dehydration.
Keep in mind that because creatine supplements increase the level of creatine in the blood, which is used as a test for kidney or renal dysfunction, doctors who are not specialists often misdiagnose patients using supplements (both protein and creatine). In short, creatine supplementation increases levels of creatinine, which can be falsely interpreted as an indication of renal dysfunction. This is because most laboratories factor in serum creatinine levels when estimating glomerular filtration rate. The frequency with which physicians who are not kidney specialists misdiagnose patients that use creatine and protein supplements with renal disease is high enough that the British Medical Journal published a “Lesson of the Week” to highlight this issue (52). Keep in mind that most studies indicate that creatine supplementation is not harmful to kidneys as long as there is not a pre-existing medical condition, and it is not mixed with medications that harm kidneys. Tell your doctor if you are taking creating, or any protein supplements, if they are sending you for kidney testing. While research is ongoing, the majority of studies conclude that creatine supplementation is generally not harmful to the kidneys when used as directed (28).
While most studies report that creatine is safe and does no harm to kidneys, there are very sporadic reports of creatine being associated with kidney damage. Keep in mind that certain prescription medications can also harm kidneys. So, it makes sense to be cautious about supplementing with if you are taking any medication that may cause kidney damage. And, creatine can interact with some medications that can harm the kidneys, potentially making the situation worse.
Nephrotoxic drugs have a creatine interaction rating of moderate, so be couscous of this if you are thinking of taking creatine. Talk with a medical professional before starting supplementation (91). Other medications that may do kidney damage are as follows(91): cyclosporine (Neoroal, Sandimmune); aminoglycosides like amikacin (Amikin); gentamicin (Garamycin, Gentak etc.) and tobramycin (Nebcin etc.); nonsteroidal anti-inflammatory drugs or NSAIDs like ibuprofen (Advil, Motrin, Nuprin etc.), indomethacin (Indocin), naproxen (Aleve, Anaprox, Naprelan, Naprosyn); piroxicam (Feldene); and many more, including Cimetidine or Tagament and Probenecid, as well as diuretics or water pills, when mixed with creatine these can increase the risk of dehydration and kidney damage (105).
Keep in mind that creatine’s effects on oxidative stress, the immune system, and inflammation, is not always good. This confluence of effects could lead, in the long term, to an immunosuppressive effect (92). That having been said, there are no long-term studies that show this to be true, perhaps because there are few long-term creatine studies using human subjects. There was a three-year study of college students (97), in which no illness was reported. But, given that these were college students, and athletes at that, there was no previous illness to be affected. It is possible that for those with a compromised immune system, creatine could make the problem worse.
Creatine may make disorders of the airway (allergy/asthma) worse. In an animal study, creatine exasperated inflammation, and an allergic reaction, in animal studies of asthma. Interestingly, research is showing that when an asthmatic does aerobic exercise and takes creatine, the exercise helps to reduce any negative side effects on breathing complications. (99). Conversely, in some cases cretine can improve lung health. Small human trials, on people suffering from Cystic fibrosis (100) and chronic obstructive pulmonary disease or COPD (101) show it provides a small positive effect on well-being, as well as on training outcomes (lifting more weight). In these studies, creatine did not impact lung functioning, probably because so little ATP is used in breathing.
1 Rawson, E.S., Clarkson, P.M.,Price, T.B., & Miles M.P., (2002). Differential response of muscle phosphocreatine to creatine supplementation in young and old subjects. Acta Physiol Scand.;174(1):57-65. DOI: 10.1046/j.1365-201x.2002.00924.x
4 Vandenberghe K,, Goris, M., Van Hecke, P., Van Leemputte, M., Vangerven, L., & Hespel, P., (1997). Long term creatine intake is beneficial to muscle performance during resistance training. J Appl Physiol (1985).;83(6):2055-63. DOI: 10.1152/jappl.1918.104.22.1685
5 Branch, J.D.,(2003). Effect of creatine supplementation on body composition and performance: a meta-analysis. Int J Sport Nutr Exerc Metab.;13(2):198-226. Accessed at: https://www.ncbi.nlm.nih.gov/pubmed/12945830
6 Graef, J. L., Smith, A. E., Kendall, K. L., Fukuda, D. H., Moon, J. R., Beck, T. W., & Stout, J. R., (2009). The effects of four weeks of creatine supplementation and high-intensity interval training on cardio-respiratory-fitness: a randomized controlled trial. Journal of the International Society of Sports Nutrition, 6, 18. DOI:10.1186/1550-2783-6-18.
7 Balsom, P.D.,Söderlund,. K, Sjödin, B., & Ekblom, B., (1995). Skeletal muscle metabolism during short duration high-intensity exercise: influence of creatine supplementation. Acta Physiol Scand.;154(3):303-10. DOI: 10.1111/j.1748-1716.1995.tb09914.x
8 Bird S. P. (2003). Creatine supplementation and exercise performance: a brief review. Journal of sports science & medicine, 2(4), 123–132.
9 Rae, C., Digney, A. L., McEwan, S. R., & Bates, T. C., (2003). Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial. Proceedings. Biological sciences, 270(1529), 2147–2150. DOI:10.1098/rspb.2003.2492.
10 Willoughby, D.S., & Rosene, J., (2001). Effects of oral creatine and resistance training on myosin heavy chain expression. Med Sci Sports Exerc.;33(10):1674-81. DOI: 10.1097/00005768-200110000-00010
11 Buford, T. W., Kreider, R. B., Stout, J. R., Greenwood, M., Campbell, B., Spano, M., & Antonio, J. (2007). International Society of Sports Nutrition position stand: creatine supplementation and exercise e. Journal of the International Society of Sports Nutrition,4, 6. DOI:10.1186/1550-2783-4-6.
12 Deldicque, L.,Theisen, D.,Bertrand, L.,Hespel, P., Hue, L., & Francaux, M., (2007). Creatine enhances differentiation of myogenic C2C12 cells by activating both p38 and Akt/PKB pathways. Am J Physiol Cell Physiol.;293(4):C1263-71. Epub 2007 Jul 25. DOI: 10.1152/ajpcell.00162.2007
16 Volek ,J.S., Kraemer, W.J., Bush, J.A., Boetes, M., Incledon, T., Clark, K.L., & Lynch, J.M., (1997). Creatine supplementation enhances muscular performance during high-intensity resistance exercise. J Am Diet Assoc.;97(7):765-70.
19 Cooke, M.B., Rybalka, E., Williams, A.D., Cribb, P.J., & Hayes, A.,(2009). Creatine supplementation enhances muscle force recovery after eccentrically-induced muscle damage in healthy individuals. J Int Soc Sports Nutr.;6:13. DOI: 10.1186/1550-2783-6-13.
21 Sarem,i A., Gharakhanloo, R., Sharghi, S., Gharaati, M.R., Larijani, B., & Omidfar, K.. (2010). Effects of oral creatine and resistance training on serum myostatin and GASP-1. Mol Cell Endocrinol.;317 (1-2):25-30. DOI: 0.1016/j.mce.2009.12.019. Epub 2009, Dec 22.
22 Lal, A.K., & Negi, K.S., (2007). Serum Creatine Kinase Activity in Thyroid Disorders Archana Prakash. Journal of Medical Education and Research, 9(1):25-26. Accessed at: http://www.jkscience.org/archive/volume91/serum.pdf
23 Sakellaris, G., Nasis, G., Kotsiou, M., Tamiolaki, M., Charissis, G., & Evangeliou, A., (2008). Prevention of traumatic headache, dizziness and fatigue with creatine administration. A pilot-study. Acta Paediatr.,97(1):31-4. Epub 2007 Dec 3.
24 McMorris, T., Harris, R.C., Swain, J., Corbett, J., Collard, K., Dyson, R.J., Dye, L., Hodgson, C., & Draper, N., (2006). Effect of creatine supplementation and sleep deprivation, with mild exercise, on cognitive and psychomotor performance, mood state, and plasma concentrations of catecholamines and cortisol. Psychopharmacology (Berl).;185(1):93-103. Epub 2006 Jan 17.
25 Dechent P, Pouwels PJ, Wilken B, Hanefeld F, & Frahm J., (1999). Increase of total creatine in human brain after oral supplementation of creatine-monohydrate. Am J Physiol.; 277(3): R698-704. DOI: 10.1152/ajpregu.1999.277.3. R698.
28 Allen P. J., (2012). Creatine metabolism and psychiatric disorders: Does creatine supplementation have therapeutic value? Neuroscience and biobehavioral reviews, 36(5), 1442–1462. DOI:10.1016/j.neubiorev.2012.03.005
30 Scandalis, T.A., Bosak, A.,Berliner, J.C., Helman. L.L., & Wells, M.R., (2001). Resistance training and gait function in patients with Parkinson’s disease.Am J Phys Med Rehabil.;80(1):38-43; quiz 44-6.
31 Hirsch, M.A., Toole, T., Maitland, C.G., & Rider, R.A., (2003). The effects of balance training and high-intensity resistance training on persons with idiopathic Parkinson’s disease. Arch Phys Med Rehabil., 84 (8):1109-17.
32 Hass, C.J., Collins, M.A., & Juncos J.L., (2007). Resistance training with creatine monohydrate improves upper-body strength in patients with Parkinson disease: a randomized trial. Neurorehabil Neural Repair.;21(2):107-15.
33 Mo, J. J., Liu, L. Y., Peng, W. B., Rao, J., Liu, Z., & Cui, L. L. (2017). The effectiveness of creatine treatment for Parkinson’s disease: an updated meta-analysis of randomized controlled trials. BMC neurology, 17(1),105. DOI:10.1186/s12883-017-0885-3
34 Kaemmerer ,W.F., Rodrigues, C.M., Steer, C.J., & Low, W.C., (2001). Creatine-supplemented diet extends Purkinje cell survival in spino-cerebellar ataxia type 1 transgenic mice but does not prevent the ataxic phenotype. Neuroscience., 103(3):713-24. DOI: 10.1016/s0306-4522(01)00017-3
35 Bürklen, T. S., Schlattner, U., Homayouni, R., Gough, K., Rak, M., Szeghalmi, A., & Wallimann, T. (2006). The creatine kinase/creatine connection to Alzheimer’s disease: CK-inactivation, APP-CK complexes and focal creatine deposits. Journal of biomedicine & biotechnology, 2006(3), 35936. DOI:10.1155/JBB/2006/35936.
36 Prass, K., Royl, G., Lindauer, U., Freyer, D., Megow, D., Dirnagl, U., Stöckler-Ipsiroglu, G., Wallimann, T., & Priller, J., (2007). Improved reperfusion and neuroprotection by creatine in a mouse model of stroke. Journal Cereb Blood Flow Metab.;27(3):452-9. Epub 2006 Jun 14. DOI:10.1038/sj.jcbfm.9600351
37 Rambo, L.M., Ribeiro, LR, Oliveira MS, Furian AF, Lima FD,Souza MA,Silva LF,Retamoso LT,Corte CL, Puntel GO, de Avila DS ,Soares F.A., Fighera, M.R., Mello, C.F., & Royes, L.F., (2009). Additive anticonvulsant effects of creatine supplementation and physical exercise against pentylenetetrazol-induced seizures. Neurochem Int.; 55(5):333-40. DOI: 10.1016/j.neuint.2009.04.007. Epub 2009 Apr 22.
39 Klivenyi, P., Ferrante, R.J., Matthews, R.T., Bogdanov, M.B., Klein, A.M., Andreassen, O.A., Mueller, G., Wermer, M., Kaddurah-Daouk, R., & Beal, M.F., (1999). Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nat Med.;5(3):347-50.
41 Op’t Eijnde, B., Ursø, B., Richter, E.A., Greenhaff, P.L., & Hespel, P., (2001). Effect of oral creatine supplementation on human muscle GLUT4 protein content after immobilization. Diabetes.;50(1):18-23.
42 Gualano. B., Novaes, R.B., Artioli, G.G., Freire, T.O., Coelho, D.F., Scagliusi, F.B., Rogeri, P.S., Roschel, H., Ugrinowitsch, C., & Lancha, A.H., Jr., (2008). Effects of creatine supplementation on glucose tolerance and insulin sensitivity in sedentary healthy males undergoing aerobic training. Amino Acids.;34(2):245-50. Epub 2007 Mar 30.
44 Cavalot, F., Petrelli, A., Traversa, M., Bonomo, K., Fiora, E., Conti, M., Anfossi, G., Costa, G., & Trovati, M., (2006). Postprandial blood glucose is a stronger predictor of cardiovascular events than fasting blood glucose in type 2 diabetes mellitus, particularly in women: lessons from the San Luigi Gonzaga Diabetes Study.J Clin Endocrinol Metab.;91(3):813-9. Epub 2005 Dec 13.
45 Roitman S, Green T, Osher Y, Karni N, & Levine J., (2007). Creatine monohydrate in resistant depression: a preliminary study. Creatine monohydrate in resistant depression: a preliminary study. Brief Report. Bipolar Disord 2007: 9: 754–758.
46 Allen, P.J., D’Anci, K. E., Kanarek, R. B., & Renshaw, P. F., (2010). Chronic creatine supplementation alters depression-like behavior in rodents in a sex-dependent manner. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology, 35(2), 534–546. DOI:10.1038/npp.2009.160.
47 Maita, L., Dr., (11/25/2014). Low Libido: Is it Low DHT. Vibrancy for Life, Your Health Unleashed website. Accessed at: https://howtoliveyounger.com/low-libido-is-it-low-dht/
48 Hull, M., (2012). Does creatine cause hair loss? Examine.com. accessed at: https://examine.com/nutriton/does-creatine-cause-hairloss/
49 McMorris T1, Mielcarz G, Harris RC, Swain JP, & Howard A., (2007). Creatine supplementation and cognitive performance in elderly individuals. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn.;14(5):517-28.
50 Smith, R. N., Agharkar, A. S., & Gonzales, E. B. (2014). A review of creatine supplementation in age-related diseases: more than a supplement for athletes. F1000Research, 3, 222. DOI:10.12688/f1000research.5218.1
51 Green, A.L., Simpson, E.J., Littlewood, J.J., Macdonald, I.A, & Greenhaff, P.L., (1996). Carbohydrate ingestion augments creatine retention during creatine feeding in humans. Acta Physiol Scand.;158(2):195-202.
52 Willis, J., Jones, R., Nwokolo, N., & Levy, J., (2010). Protein and creatine supplements and misdiagnosis of kidney disease. British Medical Journal;340: b5027.
54 Olsen, S., Aagaard, P., Kadi, F., Tufekovic, G., Verney, J., Olesen, J.L., Suetta C, & Kjaer ,M.,(2006). Creatine supplementation augments the increase in satellite cell and myonuclei number in human skeletal muscle induced by strength training.J Physiol.;573(Pt 2):525-34. Epub 2006 Mar 31.
55 Powers, M. E., Arnold, B. L., Weltman, A. L., Perrin, D. H., Mistry, D., Kahler, D. M., & Volek, J. (2003). Creatine Supplementation Increases Total Body Water Without Altering Fluid Distribution. Journal of athletic training, 38(1), 44–50.
56 Schiaffino, S., & Mammucari, C. (2011). Regulation of skeletal muscle growth by the IGF1-Akt/PKB pathway: insights from genetic models. Skeletal muscle, 1(1), 4. doi:10.1186/2044-5040-1-4
57 Burke, D.G., Candow, D.G., Chilibeck, P.D., MacNeil, L.G., Roy, B.D, Tarnopolsky, M.A., & Ziegenfuss T., (2008). Effect of creatine supplementation and resistance-exercise training on muscle insulin-like growth factor in young adults. Int J Sport Nutr Exerc Metab.;18(4):389-98.
58 Smith, A.E., Walter, A.A., Herda, T.J., Ryan, E.D., Moon, J.R., Cramer, J.T., & Stout, J.R., (2007). Effects of creatine loading on electromyographic fatigue threshold during cycle ergometry in college-aged women. Journal of Int Soc Sports Nutr.;4:20. DOI: 10.1186/1550-2783-4-20
59 Hadjicharalambous, M., Kilduff L.P., & Pitsiladis, Y.P., (2008). Brain serotonin and dopamine modulators, perceptual responses and endurance performance during exercise in the heat following creatine supplementation. J Int Soc Sports Nutr.;5:14. DOI: 10.1186/1550-2783-5-14.
60 Kilduff, L.P., Georgiades, E., James, N., Minnion, R.H., Mitchell, M., Kingsmore, D., Hadjicharlambous, M., & Pitsiladis, Y.P., (2004). The effects of creatine supplementation on cardiovascular, metabolic, and thermo-regulatory responses during exercise in the heat in endurance-trained humans. The International Journal of Sports Nutrition and Exercise Metabolism, 14(4):443-460.
61 Lyoo, I.K., Yoon, S., Kim, T.S., Hwang, J., Kim, J., Won, W., Bae, S., & Renshaw, P.F., (2012). A randomized, double-blind placebo-controlled trial of oral creatine monohydrate augmentation for enhanced response to a selective serotonin reuptake inhibitor in women with major depressive disorder. Am J Psychiatry, 169(9):937-945. DOI: 10.1176/appi.ajp.2012.12010009.
62 van der Merwe, J., Brooks, N.E., & Myburgh ,K.H.,(2009). Three weeks of creatine monohydrate supplementation affects dihydrotestosterone to testosterone ratio in college-aged rugby players. Clin J Sport Med.,19(5):399-404. DOI: 10.1097/JSM.0b013e3181b8b52f.
63 Tarride, J.E., Hopkins, R.B., Leslie, W.D., Morin, S., Adachi, J.D., Papaioannou, A., Bessette, L., Brown, J.P., & Goeree, R. (2012). The burden of illness of osteoporosis in Canada. Osteoporos Int. 23(11):2591-600.
64 Johnell, O., & Kanis, J., (2005). Epidemiology of osteoporotic fractures. Osteoporos Int. 16 (Suppl 2):S3-7.
65 Wallimann, T., & Hemmer, W., (1994). Creatine kinase in non-muscle tissues and cells. Mol Cell Biochem. 133-134:193-220.
66 Gerber, I., Gwynn, I., Alini, M., & Wallimann, T., (2005). Stimulatory effects of creatine on metabolic activity, differentiation and mineralization of primary osteoblast-like cells in monolayer and micromass cell cultures. Eur Cell Mater. 15: 10:8-22.
67 Chrusch, M.J., Chilibeck, P.D., Chad, K.E., Davison, K.S., & Burke, D.G., (2001). Creatine supplementation combined with resistance training in older men. Med Sci Sports Exerc. 33(12):2111-7.
68 Gotshalk, L.A., Kraemer, W.J., Mendonca, M.A., Vingren, J.L., Kenny, A.M., Spiering, B.A., Hatfield, D.L., Fragala, M.S., & Volek, J.S., (2008). Creatine supplementation improves muscular performance in older women. Eur J Appl Physiol., 102(2):223-31.
69 Gotshalk, L.A., Volek, J.S., Staron, R.S., Denegar ,C.R., Hagerman, F.C., & Kraemer, W.J. , (2002). Creatine supplementation improves muscular performance in older men. Med Sci Sports Exerc., 34(3):537-43.
70 Chilibeck, P.D., Sale, D.G., & Webber, C.E., (1995). Exercise and bone mineral density. Sports Med. 19(2):103-22.
71 Chilibeck, P.D., Candow, D.G., Landeryou, T., Kaviani, M., & Paus-Jenssen, L., (2015). Effects of Creatine and Resistance Training on Bone Health in Postmenopausal Women. Med Sci Sports Exerc. 47(8):1587-95
72 Lorrain, J., Paiement, G., Chevrier, N., Lalumière, G., Laflamme, G.H., Caron, P. & Fillion, A., (2003). Population demographics and socioeconomic impact of osteoporotic fractures in Canada. Menopause.,10(3):228-34.
73 Candow, D.G., Vogt, E., Johannsmeyer, S., Forbes, S.C., & Farthing, J.P., (2015). Strategic creatine supplementation and resistance training in healthy older adults. Appl Physiol Nutr Metab. 40(7):689-94.
74 Harris, R.C., Soderlund, K., & Hultman, E., (1992). Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci (Lond).,83(3):367-74.
75 Robinson., T.M, Sewell, D.A., Hultman, E., & Greenhaff. P.L., (1999). Role of submaximal exercise in promoting creatine and glycogen accumulation in human skeletal muscle. J Appl Physiol 87(2):598-604.
76 Gaffney-Stomberg, E., Insogna, K.L., Rodriguez, N.R., & Kerstetter, J.E., (2009). Increasing dietary protein requirements in elderly people for optimal muscle and bone health. J Am Geriatr Soc. 57(6):1073-9.
77 U.S. National Library of Medicine, Clinical Trails website. Webpage: Effect of Creatine Supplementation and Exercise on Bone Health Accessed at: https://clinicaltrials.gov/ct2/show/NCT02047864
78 Sekhon, L.H., Morgan, M.K., Spence, I., & Weber, N.C., (1997). Chronic cerebral hypoperfusion: pathological and behavioral consequences. Neurosurgery, 40(3):548-56
79 De Meyer, G.R., De Keulenaer, G.W., & Martinet, W., (2010). Role of autophagy in heart failure associated with aging. Heart Fail Rev. 15(5):423-30.
80 Petrovski, G., & Das, D.K., (2010). Does autophagy take a front seat in lifespan extension? J Cell Mol Med. 14(11):2543-51.
81 Terman. A, & Brunk. U.T., (2004). Lipofuscin. Int J Biochem Cell Biol. 36(8):1400-4.
82 Klopstock, T., Elstner, M., & Bender, A., (2011). Creatine in mouse models of neurodegeneration and aging. Amino Acids, 40(5):1297-303
83 Andres, R.H., Ducray, A.D., & Huber, A.W., Perez-Bouza, A., Krebs, S.H., Schlattner, U., Seiler, R.W., Wallimann, T., & Widmer, H.R., (2005). Effects of creatine treatment on survival and differentiation of GABA-ergic neurons in cultured striatal tissue. J Neurochem. 95(1):33-45. Accessed at: https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1471-4159.2005.03337.x
84 Hausmann, O.N., Fouad, K., Wallimann, T., & Schwab, M.E., (2002). Protective effects of oral creatine supplementation on spinal cord injury in rats. Spinal Cord., 40(9):449-56
85 Zhu, S., Li M., Figueroa, B.E., Liu A, Stavrovskaya I.G., Pasinelli/ P., Beal, M.F., Brown, R.H. Jr., Kristal, B.S., Ferrante, R.J., & Friedlander, R.M., (2004). Prophylactic creatine administration mediates neuroprotection in cerebral ischemia in mice. J Neurosci.24(26):5909-12
86 Andres, R.H., Ducray, A.D., Perez-Bouza, A., Schlattner, U., Huber, A.W., Krebs S.H., Seiler, R.W., Wallimann, T., & Widmer, H.R., (2005). Creatine supplementation improves dopaminergic cell survival and protects against MPP+ toxicity in an organotypic tissue culture system. Cell Transplant, 14(8):537-50. DOI: https://doi.org/10.3727/000000005783982756
87 Adhihetty, P.J., & Beal, M.F., (2008). Creatine and its potential therapeutic value for targeting cellular energy impairment in neurodegenerative diseases. Neuromolecular Med, 10(4):275-90
88 Andres, R.H., Ducray, A.D., Schlattner, U., & Wallimann, T., (2008). Widmer HR. Functions and effects of creatine in the central nervous system. Brain Res Bull.76(4):329-43
89 Zhu, S., Li, M., Figueroa, B.E., Liu, A., Stavrovskaya, I.G., Pasinelli, P., Beal, M.F., Brown, R.H. Jr., Kristal, B.S., Ferrante, R.J., & Friedlander, R.M., (2004). Prophylactic creatine administration mediates neuroprotection in cerebral ischemia in mice. J Neurosci. 24(26):5909-12. DOI:10.1523/JNEUROSCI.1278-04.2004
90 Santos, R.V., Bassit, R.A., Caperuto, E.C., & Costa Rosa, L.F., (2004). The effect of creatine supplementation upon inflammatory and muscle soreness markers after a 30km race. Life Sci.;75(16):1917-24.
91 Creatine webpage. Medicine Net website. Accessed at: https://www.medicinenet.com/creatine/supplements-vitamins.htm#SafetyConcerns
92 Riesberg, L. A., Weed, S. A., McDonald, T. L., Eckerson, J. M., & Drescher, K. M. (2016). Beyond muscles: The untapped potential of creatine. International immunopharmacology, 37, 31–42. DOI:10.1016/j.intimp.2015.12.034
93 Bassit, R.A., Curi, R., & Costa Rosa LF., (2008). Creatine supplementation reduces plasma levels of pro-inflammatory cytokines and PGE2 after a half-ironman competition. Amino Acids. 35(2):425-31. Epub 2007 Oct 4.
94 Deminice, R., Rosa, F.T., Franco, G.S., Jordao, A..A, & de Freitas, E.C., (2013). Effects of creatine supplementation on oxidative stress and inflammatory markers after repeated-sprint exercise in humans. Nutrition. 29(9):1127-32. doi: 10.1016/j.nut.2013.03.003. Epub 2013 Jun 22.
95 Deminice, R., & Jordao, A.A., (2012). Creatine supplementation reduces oxidative stress biomarkers after acute exercise in rats. Amino Acids., 43(2): 709-15.DOI: 10.1007/s00726-011-1121-x. Epub 2011 Oct 19.
96 Nomura, A., Zhang, M., Sakamoto, T., Ishii, Y., Morishima, Y., Mochizuki, M.,& Sekizawa, K., (2003). Anti-inflammatory activity of creatine supplementation in endothelial cells in vitro. British journal of pharmacology, 139(4), 715–720. DOI:10.1038/sj.bjp.0705316
97 Greenwood, M., Kreider, R.B., Melton, C., Rasmussen, C., Lancaster, S., Cantler, E., Milnor, P., & Almada, A., (2003). Creatine supplementation during college football training does not increase the incidence of cramping or injury. Mol Cell Biochem., 244(1-2):83-8.
99 Vieira, R.P., Duarte, A.C., Santos, A.B., Medeiros, M.C., Mauad, T., Martins, M.A., Carvalho, C.R., & Dolhnikoff, M., (2009). Exercise reduces effects of creatine on lung. Int J Sports Med. 30(9):684-90. DOI: 10.1055/s-0029-1224176. Epub 2009 Jun 30.
100 Braegger, C.P., Schlattner, U., Wallimann, T., Utiger, A., Frank, F., Schaefer, B., Heizmann, C.W., & Sennhauser FH., (2003). Effects of creatine supplementation in cystic fibrosis: results of a pilot study.J Cyst Fibros., 2(4):177-82.
101 Fuld,. JP., Kilduff, L.P., Neder, J.A., Pitsiladis, Y., Lean, M.E., Ward, S.A.,& Cotton, M.M., (2005). Creatine supplementation during pulmonary rehabilitation in chronic obstructive pulmonary disease. Thorax. 60(7):531-7. DOI:10.1136/thx.2004.030452).
102 Giordano, S., Darley-Usmar, V., & Zhang, J., (2013). Autophagy as an essential cellular antioxidant pathway in neurodegenerative disease. Redox Biol.2:82-90.
103 Lenz, H., Schmidt, M., Welge, V., Schlattner, U., Wallimann, T., Elsasser, H-P., Wittern, K-P., Wenck, H., Stab, F., & Blatt, T., (2005). The creatine kinase system in human skin: protective effects of creatine against oxidative and UV damage in vitro and in vivo. Journal of Investigative Dermatology 124(2): 443-452. DOI: 10.1111/j.0022-202x.2004.23522.x
104 Blatt, T., Lenz, H., Koop, U., Jaspers, S., Weber, T., Mummert, C., Wittern, K.P., Stab, F., & Wenck, H., (2005). Stimulation of skin’s energy metabolism provides multiple benefits for mature human skin. Biofactors 25(1-4):179-85. DOI: https://doi.org/10.1002/biof.5520250121.
105 Pen State University, Milton S. Hershey Medical Centre website. Webpage: creatine. Accessed at: http://pennstatehershey.adam.com/content.aspx?productid=107&pid=33&gid=000297.
106 Turner, E., McAlpine, W., Wang, K., Lu, T., Li, X., Tang, M., Zhan, X., Wang, T., Zhan, X., Bu, C.H., Murrayare., and Butler, B.,(2016). Creatine maintains Intestinal homeostasis and protects against colitis. PNAS, E1273-E1281. DOI:10.1073/pnas1621400114.
107 Colgan, S. P., Curtis, V. F., Lanis, J. M., & Glover, L. E. (2015). Metabolic regulation of intestinal epithelial barrier during inflammation. Tissue barriers, 3(1-2), e970936. DOI:10.4161/21688362.2014.970936).
108 Roy, A., & Lee, D. (2016). Dietary Creatine as a Possible Novel Treatment for Crohn’s Ileitis. ACG case reports journal, 3(4), e173. DOI:10.14309/crj.2016.146.
109 Moreira, P.I., Cavalho, C., Zhu, X., Smith, M.A., & Perry, G., (2010). Mitochondrial dysfunction is a trigger of Alzheimer’s Disease pathophysiology. Biochim Biophys Acta., 1802(1):2-10.
110 Klein, A.M., & Ferrante, R.J., (2007). The neuroprotective role of creatine. Subcell Biochem., 46:205-243.
111 Brewer, G.J., & Walliman, T.W., (2000). Protective effect of the energy precursor creatine against toxicity of glutamate and beta-amyloid in rat hippocampal neurons. J. Neurochem, 74(5): 1968-1978.
112 Soares, V. P., & Campos, A. C., (2017). Evidences for the Anti-panic Actions of Cannabidiol. Current neuropharmacology., 15(2): 291–299. DOI:10.2174/1570159X14666160509123955.
113 Bender, A., Beckers, J., & Schneider I., et al., (2008). Creatine improves health and survival of mice. Neurobiol Aging., 29(9): 1404-1411.
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