@smok said in Over-methylation:
On the subreddits r/Nootropics and r/Supplements there's hundreds of posts on the cholinergics Choline, Alpha-Gpc causing serious depression in their users.
Possibility when in excess.
After a search with LucH pendulum 😉 , here is what I've fund:
Too much choline ?
Can too much acetylcholine cause depression?
Acetylcholine normally enhances cortical sensitivity to external stimuli and decreases corticocortical communication, increasing focused attention. However, increases in ACh signaling can lead to symptoms related to anxiety and depression.
What about prescribing a supplement of αGPC?
Alpha-glycerylphosphorylcholine (αGPC) is a precursor of acetylcholine and can increase acetylcholine concentration in the brain.
=> Neuromodulation by Acetylcholine.
Side effects:
Alpha-GPC seems to be safe when used appropriately. It can cause side effects in some people including heartburn, headache, insomnia, dizziness, skin rash, and confusion. Possibly excess choline (20 g) can also include depression and heart rhythm problems. Choline may cause depression in some people.
Can you take choline and Alpha-GPC together?
These two choline supplements work well together. The synthesis of acetylcholine (ACh) is largely dependent on the choline provided by phosphatidylcholine (PC). Alpha GPC is a byproduct of phosphatidylcholine (PC). And supplemental CDP-Choline provides the uridine needed for PC synthesis.
Does Alpha-GPC affect dopamine?
Treatment with αGPC increases dopamine levels as well as dopamine active transporter expression in the frontal cortex and cerebellum [10]. It also increases serotonin levels in the frontal cortex and striatum of rat brains [10].
10. doi: 10.2174/1871527311312010015
Does choline affect estrogen?
Estrogen stimulates the breakdown of phosphatidylcholine (cell membrane) so those with low estrogen (postmenopausal women) require more choline. Detoxify excess estrogen via the methylation pathway.
Does choline affect your mood?
Low levels of choline are also associated with depressive symptoms — likely because choline is a precursor to the nutrient known as betaine. Betaine reduces homocysteine levels in the body, and high homocysteine has been linked to depression (particularly in men). 2023
Note from Luc on side effects on High Dose PLP (B6)
See “English Corner – Vit B6: How much is too much?”
https://mirzoune-ciboulette.forumactif.org/t2033-english-corner-vit-b6-how-much-is-too-much#29628
An excess of B6 could induce choline-like effects of deprivation. PLP encounters a barrier when in excess.
An excess of Pyridoxal will lead to the inhibition of the enzyme PLK (Pyridoxal Kinase). PLK is set out of function via the “Salvage pathway” process. Note that this observation has been “recorded” only in 2021. It was not rigorously established up to then. But, it already seemed logical / acceptable to me.
Attempted explanation by researchers:
In case of supplementation with a high dose of Vit B PLP – activated vitamin B6 – or in the event of upstream malfunction (coupling / decoupling process for the transfer to the cell), a protective mechanism occurs in order to control the cell levels of PLP. (6-7)
Pyridoxal (PL) is inhibited by Pyridoxal Kinase (PLK) during a regulating process related to the B6 metabolism. The inactivation process (inhibition of Vit B6 PLP) is a protective mechanism when there is too much PLP in circulation. The cause remains uncertain; the possibilities would include aldehyde stress from the degraded / neutralized PLP molecule. Pathology mimics then the symptoms of a lack of vitamin B6.
