How does creatine get into the brain?
Creatine reaches the brain via a single specific transport protein in the blood-brain barrier. In people with a normally functioning transport system, oral supplementation may modestly top up brain stores, though this happens much more slowly and to a far lesser extent than in muscles.
Creatine cannot simply enter the brain. The blood-brain barrier, the protective wall separating the blood from brain tissue, only lets creatine through via a dedicated transport protein. That protein actively pumps creatine from the blood into the brain. Without a working transporter, the brain remains low in creatine, even when there is plenty of creatine circulating in your blood.
Animal studies show just how decisive this transporter is. In mice in which the gene for the creatine transporter had been switched off, creatine levels in the blood, liver and kidneys rose substantially after 30 days of oral supplementation, but creatine levels in the brain remained unchanged and low. This makes one thing clear: the transporter is the only relevant entry point.
In people born with a defect in that transport protein, the effect is far more dramatic. Such a defect leads to a severe shortage of creatine in the brain, resulting in intellectual disability, speech problems and often epilepsy. Taking creatine by mouth does not help the brain in these cases, even though the rest of the body does benefit.
For people with a normally functioning transport protein, the picture is more nuanced. A small study in 36 women around the time of menopause found that 1,500 mg of creatine per day for 8 weeks stabilised creatine levels in the front part of the brain, while levels in the group not taking creatine fell by more than 16%. This is an early indication that taking creatine by mouth can have some effect on brain creatine, but the finding is preliminary and based on a small group.
A practical note: creatine levels in red blood cells do not reflect what is happening in the brain. Red blood cells do carry many creatine transporters, but the additional barrier posed by the blood-brain barrier makes them an unreliable measure of how much creatine the brain is actually receiving. This also helps explain why studies on creatine and thinking ability show mixed results: uptake into the brain is far less predictable than uptake into muscles.
This answer draws on two reviews, animal studies using genetically modified mice, a study in people with a creatine transporter deficiency, and one small study in 36 women. The way the creatine transporter works is well documented biologically and is confirmed by the striking picture seen in people with a faulty transporter. The evidence for how well oral supplements are taken up in healthy people is early-stage: the only relevant study is small and was not large enough to detect reliable differences.