Homocysteine is produced after S-adenosyl methionine is used up (as donating a methyl group creates S-adenosylhomocysteine, which then produces homocysteine) mostly from phosphatidylcholine synthesis[307] and its reduction (via either methylation from trimethylglycine via betaine:homocysteine methyltransferase, urinary excretion, or convertion into L-cysteine via cystathionine beta-synthase[308]) is thought to be therapeutic for cardiovascular diseases.

In young rats given creatine in the diet at 2% of the diet for eight weeks, supplementation appears to increase bone mineral density (BMD) in the lumbar spine with a nonsignificant trend to increase BMD in the femur.[426] Despite the trend, the femur appeared to be 12.3% more resistant to snapping from mechanical stress associated with increased thickness.[426] Menopausal rats (ovarectomized) experience similar benefits, as supplementation of creatine (300mg/kg) for eight weeks during ovarectomy is able to increase phosphorus content of the bone and other biomarkers of bone health, although bone stress resistance was not tested.[427]
Safety. In general health terms, most medical opinion is that up to three cups of coffee a day are not harmful, and may even have some benefits, although some people respond to the stimulant properties with more problems than others. Heart palpitations and restlessness are experienced by some caffeine drinkers. In pregnancy, one or two cups each day are thought to be without harm to the fetus.

It is known that intracellular energy depletion (assessed by a depletion of ATP) stimulates AMPK activity in order to normalize the AMP:ATP ratio,[333][334] and when activated AMPK (active in states of low cellular energy[335] and colocalizes with creatine kinase in muscle tissue[336]) appears to inhibit creatine kinase via phosphorylation (preserving phosphocreatine stores but attenuating the rate that creatine buffers ATP). While phosphocreatine technically inhibits AMPK, this does not occur in the presence of creatine at a 2:1 ratio.[334] It seems that if the ratio of phosphocreatine:creatine increases (indicative of excess cellular energy status) that AMPK activity is then attenuated, since when a cell is in a high energy status, there is less AMP to directly activate AMPK.[334][336][337]
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