Creatine
Creatine featured article
Creatine is a naturally occurring compound that is critical in storing and releasing cellular energy. It also participates in many biological processes driving pregnancy outcomes, maintaining bone mineral density and muscle mass in older adults, improving neurological function, and aiding the immune system to fight cancer. Creatine is best known for its widespread use as a dietary supplement to enhance physical performance.
Creatine uptake, synthesis, storage, and supplementation
Creatine uptake
Creatine can be supplied exogenously (from dietary or supplemental sources) and taken directly into cells by the creatine transporters designated CreaT1 and CreaT2. Dietary sources of creatine include meat, such as red meat and poultry, as well as fish. Meat contains approximately 4 to 5 grams of creatine per kilogram of the animal's weight, while fish contains approximately 4 to 10 grams per kilogram. However, creatine converts to creatinine when heated, so estimates of...
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Dr. Rhonda Patrick discusses beta-glucan fiber for PFAS reduction, creatine and caffeine, urolithin A, exogenous ketones, IVF supplements, Botox, and sauna.
Dr. Rhonda Patrick discusses child nutrition, osteoporosis, cholesterol-lowering supplements, her skincare routine, and fasting versus prioritizing protein.
Jet lag often shows up as fatigue after a long flight, reflecting a mismatch between your internal clock and the external...
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Rhonda Pollution Fiber Sauna Caffeine Supplements Urolithin A Creatine Reproductive Health Exogenous KetonesDr. Rhonda Patrick discusses beta-glucan fiber for PFAS reduction, creatine and caffeine, urolithin A, exogenous ketones, IVF supplements, Botox, and sauna.
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Dr. Rhonda Patrick discusses child nutrition, osteoporosis, cholesterol-lowering supplements, her skincare routine, and fasting versus prioritizing protein.
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Jet lag often shows up as fatigue after a long flight, reflecting a mismatch between your internal clock and the external...
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Dr. Rhonda Patrick discusses protein needs, choline in pregnancy, urolithin A, melatonin's benefits and risks, and creatine's effects on liver health.
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Creatine is best known as a muscle supplement, but a new study examined whether it can also support immune cells involved in cancer defense. The researchers focused on dendritic cells, a type of immune cell that helps alert the immune system by presenting antigen fragments from viruses, bacteria, and tumors to T cells, which can then mount responses against infected or abnormal cells.
The work combined cell experiments with an animal tumor model. In mouse dendritic cells, the researchers tested whether the ability to take up creatine affected cell survival, immune signaling, and the activation of T cells. They did this by comparing cells with and without the protein that transports creatine into cells, and by examining how the cells responded to additional creatine. Human dendritic cells grown from blood samples were then used to test whether creatine produced similar immune-enhancing effects. Finally, mice implanted with melanoma cells received creatine injections to determine whether these cellular changes translated into differences in tumor growth and immune activity within tumors.
- Mouse dendritic cells made more of the creatine transporter when they switched into an active immune state, both in cells grown outside the body and in cells taken from tumors.
- Mouse dendritic cells without the creatine transporter were less likely to survive, produced fewer inflammatory signals, showed weaker immune-alert markers, and had lower ATP, the molecule cells use as a direct energy source.
- Creatine-treated dendritic cells survived better, showed stronger immune-alert markers, turned on more inflammatory-response genes, and had higher levels of ATP.
- Human dendritic cells produced stronger inflammatory signals after creatine treatment and were better able to activate T cells designed to recognize a tumor protein.
- In the melanoma model, creatine-treated mice had slower tumor growth, and dendritic cells inside the tumors showed stronger signs of immune activity, especially in a subtype that helps present tumor material to T cells.
The results suggest that creatine may help supply the energy needed for dendritic cell activation. Once inside cells, creatine can be converted into phosphocreatine, a stored form of energy support that helps maintain ATP availability. That extra energy support may help dendritic cells send inflammatory signals, display tumor material more effectively, and activate T cells.
Because the study was only done in cells and mice, it does not show whether creatine would have the same effects in human cancer patients. If confirmed in clinical trials, creatine could become a simple and inexpensive way to support immunotherapy strategies for cancer treatment. In episode #100, Dr. Darren Candow breaks down the optimal creatine protocol for supporting strength, brain health, and longevity.
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A single 14-gram dose of creatine helped preserve cognitive performance after a sleepless night. doi.org
High doses of creatine have recently been shown to help preserve cognitive performance during acute sleep deprivation, but it is less clear whether a lower dose can provide similar benefits.
A new study included 29 healthy adults aged 20 to 40 in a crossover trial. Each participant completed two separate sleepless nights in random order, receiving a single dose of 0.2 grams of creatine monohydrate per kilogram of body weight (0.2 g/kg; about 14 grams on average) on one night and a placebo on the other. Participants stayed awake from about 7 a.m. until around 4:30 a.m. the next morning. Cognitive testing was performed several times throughout the sleep-deprivation period, with creatine or placebo given after about 14 hours of wakefulness.
- The clearest benefit was on reasoning questions. Across the three overnight tests, participants scored 6.1% higher with creatine than with placebo after accounting for their starting scores. On the placebo night, reasoning performance fell by 6.8%.
- A few other measures also leaned in favor of creatine compared with placebo, but the evidence was statistically less robust. Participants scored 6.2% higher on numerical reasoning questions, answered verbal questions 12.3% faster, and had 9.2% less variation in their reaction times, while average reaction speed changed little.
- Creatine did not clearly reduce sleepiness or fatigue compared with placebo. By 4 a.m., sleepiness had risen 155% from the 6 p.m. baseline measure with creatine and 173% with placebo. Fatigue also rose in both conditions, by 148% with creatine and 115% with placebo.
- Not every measure improved with creatine: word memory, memory for number sequences, the ability to briefly hold visual information in mind, and language accuracy were not clearly better than with placebo.
Creatine supports cellular energy through the creatine kinase and phosphocreatine system, which helps regenerate ATP, the main energy molecule used by cells. Sleep deprivation is a stress condition that may strain energy reserves and make creatine uptake more relevant than it would be after a restful night, especially during demanding cognitive tasks. This could explain why creatine modestly helped preserve performance during the sleepless night, even though participants still felt increasingly sleepy and fatigued.
This was a small, one-night study in healthy young adults, so it is unclear how well the findings would apply outside this controlled setting. Still, the results suggest that creatine may help preserve some aspects of cognition during sleep loss even at 0.2 g/kg, although the effects appeared less pronounced than in earlier work from the same group using 0.35 g/kg. In this clip, I explain why I increased my creatine intake and how creatine may support brain energy during sleep loss and mid-afternoon dips.
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Depression research often focuses on neurotransmitters, but the brain also depends on a steady supply of energy to function properly. A new study tested whether problems in how creatine moves from the gut to the brain play a role in depression, and whether certain gut bacteria can help restore this process.
To examine this, researchers combined human data with experiments in mice and cell models. They compared adults with major depressive disorder (MDD) to healthy controls, and mice that developed depression-like behaviors during chronic stress to unstressed control mice, using metabolite profiling (measurement of small molecules involved in metabolism), along with behavioral testing, gut microbiome manipulations, genetic models, and a small, 28-day pilot study in MDD patients taking antidepressants (SSRIs).
- Broad metabolite profiling revealed differences in metabolism between MDD patients and healthy controls, and between mice with depression-like behavior and control mice, with creatine emerging as a key altered molecule.
- People with MDD and mice with depression-like behavior had more creatine in feces but less in blood plasma and in the cerebrospinal fluid (liquid that surrounds the brain and spinal cord). In mice with depression-like behavior, creatine was also lower in the medial prefrontal cortex, a brain region involved in mood and decision-making.
- Creatine improved several depression-like behaviors in mice. It reduced how long the animals remained passive in stress-based tests, improved social interaction, and increased preference for sweet solutions, a common measure of motivation or pleasure-related behavior in animals. These effects were not due to increased overall activity, as creatine did not make the mice more active in general.
- When the gut microbiome was depleted with antibiotics, or replaced with microbes from MDD patients, mice showed a smaller rise in blood creatine after supplementation and lost much of creatine's behavioral benefit.
- The bacterium Bifidobacterium pseudolongum was found at lower levels in MDD patients and in mice that received gut microbes from MDD patients. Mice that had more of this specific gut bacterium also tended to have more creatine in their plasma.
- Bifidobacterium pseudolongum increased levels of the creatine transporter Slc6a8 in intestinal cells, supporting creatine uptake from the gut. This effect was observed in mice and reproduced in human intestinal cells using compounds produced by the bacteria, with acetate identified as a key contributing factor.
- Removing this creatine transporter at the blood–brain barrier and in nerve cells in mice disrupted creatine's effects on behavior, while additional nerve cell experiments showed reduced energy production and impaired neuronal activity when Slc6a8 was absent.
- In the human pilot study, among those MDD patients who completed the experiment, receiving a combination of Bifidobacterium adolescentis (a related strain with established applications in food and medicine) and creatine was associated with greater reductions in depression scores than placebo.
The data point to a disrupted gut–brain energy pathway in depression. Creatine supports cellular energy by helping regenerate ATP, the molecule that powers cellular activity, so reduced availability in the brain could impair normal function. Gut bacteria appear to regulate this pathway: B. pseudolongum and B. adolescentis produce acetate, a short-chain fatty acid that increases levels of the transporter that allows intestinal cells to take up creatine, thereby supporting its absorption into the bloodstream. Creatine must then cross the blood–brain barrier and enter nerve cells to support energy production and signaling. Disrupting this transporter at these steps prevented creatine's behavioral effects, indicating that impaired transport along this pathway may contribute to depression, while restoring it could help improve symptoms.
If this potentially synergistic effect of creatine and specific probiotics is confirmed in larger, well-controlled human trials that compare the effects of creatine and probiotics individually to their combination and placebo, targeting this gut–brain energy pathway could offer a new approach to improving depression treatment. In Aliquot #133, Dr. Candow and I discuss the surprising brain benefits of creatine.
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Many women going through menopause describe feeling mentally slower or more fatigued, a phenomenon often called "brain fog". Researchers in Serbia explored whether small daily doses of creatine could ease these symptoms and improve brain function.
The study included 36 healthy women around 50 years old, half of whom were menopausal and half perimenopausal. Over eight weeks, participants took creatine capsules twice daily for eight weeks, totaling 750 mg or 1,500 mg of creatine hydrochloride per day, or a combination providing 400 mg of creatine hydrochloride plus 400 mg of creatine ethyl ester per day, or a placebo.
Here is what the researchers found:
- Low-dose creatine hydrochloride (750 mg/day) improved alertness, executive control, and information-processing speed. Women reacted roughly 5–6 percent faster on attention tasks compared with baseline, while the placebo group became about 1 percent slower.
- Medium-dose creatine hydrochloride (1,500 mg/day) improved reaction time by 6.6 percent from baseline, compared with a 1.2 percent change in the placebo group. It also reduced general fatigue by about 14 percent and concentration difficulties by about 48 percent, with a trend toward fewer mood swings.
- The combination of creatine hydrochloride and creatine ethyl ester (800 mg total/day) improved attention and reaction speed on a cognitive task, and uniquely lowered self-reported anxiety by about 39 percent.
- Brain scans showed that all creatine treatments increased total creatine across multiple regions, with notable increases in frontal areas, which are involved in focus and decision-making. For example, right frontal white matter creatine rose by roughly 16 percent in the medium-dose group compared with less than 1 percent in the placebo group.
Creatine helps recycle adenosine triphosphate (ATP), the molecule that powers most cellular activity. The authors suggest that menopause-related hormonal and metabolic changes might make women particularly responsive to creatine's energy-stabilizing effects. Even at these low doses, brain creatine rose measurably—possibly because of improved absorption or slower clearance during this life stage.
Although the findings point to a safe and practical way to support attention, mood, and brain creatine levels during menopause, the trial was small, lasted only eight weeks, and included brain scans from just 16 participants. Larger, longer studies are needed to confirm these results and determine how different creatine formulations and doses might best support women's brain health. Explore the optimal creatine protocol for ftrength, brain, and longevity in episode #100, featuring Darren Candow, PhD.