Which form of folate reaches the brain most effectively?
In a folate transport disorder, folinic acid reaches the brain most effectively via alternative routes. For most people, the type of folate probably makes little difference for brain uptake.
Folate does not reach the brain equally well through every route. There are three transport routes: one sits in the brain membrane, one in the gut wall and blood-brain barrier, and one works via a small acid. Which form of folate works best depends on which of these routes functions well in your body.
Standard folic acid, the synthetic supplement found in most pills, is the common choice for healthy people, but the body converts it only slowly through a liver enzyme. As a result, unprocessed folic acid builds up in the blood. Whether this causes harm in itself has not been established, but it is one reason some researchers prefer the already-converted form: 5-methylfolate (folic acid your body has already prepared for use).
In people whose transport route through the brain membrane works poorly, because of an inherited condition or because their own immune system blocks that route, folinic acid is the appropriate form. Folinic acid reaches the brain through the two other transport routes, bypassing the problem. In the rare inherited condition where the brain membrane route fails completely, folinic acid at a high dose restores folate levels in the fluid surrounding the brain. Starting early prevents or limits neurological damage.
Standard folic acid is explicitly discouraged in these rare conditions. It clings to the already defective transport route and can further block whatever small function remains. The same concern applies to another transport disorder in which folate absorption in the gut does not work properly. In those situations, 5-methylfolate or folinic acid are the better choices, but higher levels in the blood are probably needed for enough folate to reach the brain.
For healthy people without a transport disorder, no proven difference in brain uptake has been shown between the available forms. Choosing 5-methylfolate over standard folic acid is then about avoiding unprocessed folic acid in the blood, not about proven better brain uptake. If you have reason to suspect a folate transport problem, discuss this with your doctor, because the right form of folate differs depending on the diagnosis.
This answer draws mainly on reviews and case series on rare inherited folate transport disorders, a small study of 16 children on prenatal folinic acid in pregnancies testing positive for a brain membrane transport antibody, and a small review of three studies on 5-methyl folate and unmetabolised folic acid (evidence quality: low). The researchers in the small prenatal study all worked at the same clinic, which is a potential conflict of interest. For healthy people without a transport disorder, there is very little direct research into which form of folate reaches the brain most effectively.
Can too much vitamin B6 cause neuropathy or numbness?
Vitamin B6 supplements above 50 mg per day can cause nerve damage with long-term use. Stick to the recommended dose on the label and speak to your doctor if you develop tingling or numbness.