Creatine
Creatine and Cardioprotection 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, phosphocreatine, creatine transporters, and creatine kinase enzymes are expressed in the endothelial cells that line our blood vessels and play an integral role in delivering high-energy phosphates to ion channels that maintain vascular tone and regulate endothelial function. Creatine may positively impact vascular health through several mechanisms, including its role as an antioxidant, its effects on nitric oxide (NO) bioavailability, its support of endothelium-derived hyperpolarization factors...
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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...
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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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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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.
For 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 resilient control mice, using metabolite profiling (measurement of small molecules involved in metabolism), along with behavioral testing, microbiome manipulations, genetic models, and a small, 28-day pilot study in humans to investigate the underlying biology.
- 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 cerbrospinal 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 and improved social interaction and interest in sweet drinks, a common way to measure motivation or pleasure 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 with depression-like behavior. In mice, higher levels of this bacterium were also associated with higher creatine levels in blood plasma.
- Bifidobacterium pseudolongum increased levels of the creatine transporter Slc6a8 in intestinal cells, supporting creatine uptake from the gut, an effect seen in mice and reproduced in human intestinal cells using bacterial products, 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 weaker signaling when Slc6a8 was absent.
- In the human pilot study, 45 MDD patients taking antidepressants (SSRIs) who received a combination of Bifidobacterium adolescentis (a closely related strain with established applications in food and medicine) and creatine showed larger increases in plasma creatine and greater reductions in depression scores than those given 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 small molecule that increased 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 tranpsorter 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 suprising 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.