This question of what high P5P in blood actually means is very interesting - it could mean that too much B6 is being ingested and hence that neurotoxicity is likely, or it could mean too little is being taken up by cells and thus that a functional deficiency is likely. How do you tell the difference? I've tried to read up on this (when my worsening brain fog allows) and have concluded that there is far too little research and it can only be determined empirically, although an OAT test would give some insight into a likely functional deficiency. A P5P test by itself means very little. The neurotoxicity literature was particularly disappointing. There really are only a few studies which showed that high levels of P5P tended to be associated with neurotoxicity but not necessarily, and nothing much about mechanism. There is a secondary issue of which form of supplementary vitamin to take - is P5P better or somehow more protective from neurotoxicity? As @MacGyver notes, for P5P in the blood to be taken into cells, alkaline phosphatase is necessary to remove the phosphate group because the B6 transporter carries only the unphosphorylated form. Once inside the cell, a kinase enzyme puts the phosphate group back thus making the active vitamin again inside the cell (where it stays since the transporter won't carry it out with a phosphate present). Before this, in the gut, AP activity is also necessary to allow phosphorylated forms of the vitamin from food and supplements to be absorbed. The liver then makes the active phosphorylated P5P and dumps it into the blood where it is available for uptake by cells, after appropriate processing. You might ask what then is the point of taking expensive active B6 supplements since the body has to remove the phosphate before they can be used. Well, the story is a bit more complicated because it appears that there is at least some direct uptake of the phosphorylated form of the vitamin, probably by endocytosis. Also it appears (though there is not a lot of good evidence for this) that P5P supplements might be 5 times more active, weight for weight, than the more usual pyridoxine supplements. So how a person responds to B6 supplementation, whether P5P or pyridoxine or some combination thereof, is the result of their own individual combination of direct P5P endocytotic capacity as well as phosphatase and kinase activities. One or the other form is not necessarily better, it all depends on the individual and can only be determined empirically. Getting back to the basic issue of what high plasma P5P means, as I mentioned in my post a few months ago, in light of some of the info in this thread I decided to do some experimenting with B6. I can now report that, despite my high P5P, reducing B6 has not been a good idea. I think I definitely fall into category where it means functional deficiency. An OAT test also shows deteriorating oxalate markers and elevated kynurenic acid, both B6 related. Interestingly, as time has gone by I have found myself become intolerant of magnesium (in my case nothing to do with boron since I have continued to take a trace mineral supplement containing 0.7 mg boron daily) as well as methyl folate and methyl B12 and have had to reduce my intake of all considerably. I can't necessarily attribute this to an increasing functional B6 deficiency since my overall condition has been deteriorating since before I started experimenting with B6 (the decline was of course part of the reason I was casting around for different things to experiment with) but the coincidence seems very suspicious to me. I am going to start increasing B6 again.